AU715202B2

AU715202B2 - Inhibitors of farnesyl-protein transferase

Info

Publication number: AU715202B2
Application number: AU27347/97A
Authority: AU
Inventors: Neville J Anthony; Ian M. Bell; Christopher Dinsmore; Mark W. Embrey; Thorsten E Fisher; Robert P Gomez; John H. Hutchinson; John S. Wai; Theresa M. Williams
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1996-04-03
Filing date: 1997-03-27
Publication date: 2000-01-20
Anticipated expiration: 2017-03-27
Also published as: EP0944388A4; EP0944388A2; WO1997038665A2; AU2734797A; WO1997038665A3; JP2001519766A; CA2249601A1

Description

WO 97/38665 PCT/US97/06487 -1- TITLE OF THE INVENTION INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE BACKGROUND OF THE INVENTION The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminktd by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form Lowy and D.M.

Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in maly-human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal., Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involvecJath Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaal-Aaa 2 -Xaa" box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively. Clarke., Ann. Rev. Biochem. 61:355-386 (1992); W.R. Schafer and J. Rine, Ann.

Rev. Genetics 30:209-237 (1992)). The Ras protein is one of several proteins that are known to undergo post-translational farnesylation.

WO 97/38665 PCT/US97/06487 -2- Other farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.

Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of rasdependent tumors in nude mice Kohl et al., Proc. Natl. Acad. Sci 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice Kohl et al., Nature Medicine, 1:792-797 (1995).

Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of farnesylprotein transferase would be more specific and attended by fewer side WO 97/38665 PCT/US97/06487 -3effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.

Inhibitors of farnesyl-protein transferase (FPTase) have been described in two general classes. The first are analogs of farnesyl diphosphate (FPP), while the second class of inhibitors is related to the protein substrates Ras) for the enzyme. The peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S.

Patent 5,141,851, University of Texas; N.E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).

In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound.

However, the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.

It has recently been reported that farnesyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7- 112930).

It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516).

Imidazole-containing inhibitors of farnesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 Al).

It is, therefore, an object of this invention to develop peptidomimetic compounds that do not have a thiol moiety, and that will inhibit farnesyl-protein transferase and thus, the post-translational farnesylation of proteins. It is a further object of this invention to WO 97/38665 PCT/US97/06487 -4develop chemotherapeutic compositions containing the compounds of this invention and methods for producing the compounds of this invention.

SUMMARY OF THE INVENTION The present invention comprises piperidine-containing compounds which inhibit the farnesyl-protein transferase. The instant compounds lack a thiol moiety and thus offer unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, suchas rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

The compounds of this invention are illustrated by the formula A:

(R

8 )r 9)R2

R

1r b\ N )-IX Y V A'(CRa 2 )nA 2 (CRla 2 n W -(CR b 2 -K CR^ Z

R

4

R

A

(R

8 r R2

R

3 V A'(CRa 2

)A

2 (CRa 2 n W (CRb 2

/N-(CR

1 2 )v-Z

R

4

R

B

WO 97/38665 PCT/US97/06487 DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the farnesylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula A:

(R

8 )r (R 9 )q R 2 V- A'(CRa 2 )nA 2 (CRa 2 )W (CRlb 2 )p\X A t 2/ X X-(C Ric2)- Z

R

4

R

A

wherein: Rla and R 1 b are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, R 10

R

1 1 R10C(O)NR10-, (R10)2N- CN, N02, (R10)2N-C(NR 10 R10C(O)-, N3, -N(R10)2, or R 1 1

OC(O)NR

1 0 c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, Rl R 10

C(O)NR

10

(R

10

CN,

(R

10 )2N-C(NR10)-, RO1C(O)-, N3, -N(R 10 and

R

1 1

OC(O)-NR

10 Rlc is selected from: a) hydrogen, b) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, WO 97/38665 WO 9738665PCTIUS97/06487 -6-

R

1 1 R I C(O)NR 1 0 (R 10

CN,

(R

1 0 )2N-C(NRIO)-, RIOC(O)-, R 10 N3, -N(R 10 and R I I0C(O)-NR 1 and c) unsubstituted or substituted aryl;

R

2 and R 3 are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or R or e R substituted heterocycle, OR 10 0 0 wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Cl1-4 alkyl, b) (CH2)pOR 6 c) (CH2)pNR 6

R

7 d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C 1 -4 alkyl, h) SR 6 a, S(O)R 6 a, SO2R 6 a, 2) C3-6 cycloalkyl, 3) OR 6 4) SR 6 a, S(O)R 6 a, or SO2R 6 a, -NR 6 R 7 R 6 6) -N 0 -N

NRRY

0 WO 97/38665 PCT/US97/06487 -7- 8) O

NR

6

R

7 0 9) O OR 6

O

0

NR

6

R

7 0 11) -SO2-NR 6

R

7

R

6 12) -N-SO2-R6a 13)

R

6

O

14) OR6 0

N

3 16) F, or 17) perfluoro-C-.

4 -alkyl; or

R

2 and R 3 are attached to the same C atom and are combined to form (CH2)u wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and

R

4 and R 5 are independently selected from H and CH3; and any two of R 2

R

3

R

4 and R 5 are optionally attached to the same carbon atom; WO 97/38665 PCT/US97/06487 -8-

R

6

R

7 and R7a are independently selected from: CI-4 alkyl, C3-.6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Ci -4 alkoxy, b) unsubstituted aryl, substituted aryl, unsubstituted heteroaryl or substituted heterocycle, c) halogen, d) HO, e)

"YR

11 0 f) -S0 2

R

11 ,or g) N(RlO)2; or

R

6 and R 7 may be joined in a ring;

R

7 and R 7 a may be joined in a ring;

R

6 a is selected from: Ci1 -4 alkyl, C3-.6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) C 1 -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e)

'YR

0 f) -S0 2

R

1 or g) N(RlO)2;

R

8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, WO 97/38665 WO 9738665PCTIUS97/06487 -9- RlOC(0)NR 10-, (RI 0 R 10 2N-C(NR CN, N02, R IOC(0)-, N3, -N(R'1O)2, or R I IOC(0)NR10-, and c) C I -C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, periluoroalkyl, F, Cl, Br, RIO0-, R I 1 S R 1 C(0)NH-, (R I R I 0 2N- C(NRIO)-, CN, RIOC(0)-, N3, -N(R 1 0 or

R

1 OOC(0)NH-; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 100.., R I R 1 I C(0)NR 10 (R 1 02NC(0)-,

R

1 0 2N-C(NRIO)-, CN, N02, RIOC(0)-, N3, -N(RIO)2, or R I I0C(O)NR 1 and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 RI IS R I C(0)NR (RIO)2NC(O)-,

R

10 2N-C(NRIO)-, CN, RIOC(0)-, N3, -N(IO2,or R 1 1

OC(O)NRIO-;

R

10 is independently selected from hydrogen, Cl-C14 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl; R 1 1is independently selected from Ci1 -C6 alkyl and substituted or unsubstituted aryl;

R

1 2 is selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted alkyl, substituted aryl or substituted heterocycle is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Cl1 -4 alkyl, b) (CH2)pOR 6 WO 97/38665 WO 9738665PCTIUS97/06487 10 c) (CH2)pNR 6

R

7 d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C 1-4 alkyl, h) SR 6 a, S(O)R 6 a, SO2R 6 a, 2) C3-6 cycloalkyl, 3) OR 6 4) SR 6 a, S(O)R 6 a, or SO2R 6 a, -NR 6 R 7 R 6 6) 7 0 7)-N y NR Ra 0 8) -0O NR 6 R 7 0 9) -O OR 6 0 'YNR 6 R 7 0 11) -S0 2 -NR 6 R 7 R 6 12) -N-SO 2 -Ra WO 97/38665 WO 9738665PCTIUS97/06487 13) rR 6 0 14) -,OR 6 0

N

3 16) F, 17) perfluoro-Cl- 4 -alkyl, or 18) C 1 l.

6 -alkyI;

A

1 I and A 2 are independently selected from: a bond, -CH=CH-, -CR=C-, -C(O)NRIO-, -NRIOC(O)-, 0, -N(RIO)-, -S(0)2N(R] 0 -N(RIO)S(0)2-, or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) CI -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from 0, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X is a bond, -CH2-, -NR 6 or X1 is a bond, -NR 6

-NR

6 or Y is selected from: a) hydrogen, WO 97/38665 WO 9738665PCT/US97/06487 12 b) R 1 0

R

1 IS(O)m-, RlGC(O)NR 10

(R

1

CN,

N02, (R 1 0 )2N-C(NRIO)-, R 1 2

R

1 0 N3, F, 102,or R1 1 0C(O)NR 1 and c) unsubstituted or substituted C I -C6 alkyl wherein the substitutent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, R 10 R IOC(O)NR 1 0-,

(R

1 0 RIOC(O)- and RIO0C(O)-; Z is an unsubstituted or substituted group selected from aryl and heterocycle, wherein the substituted group is substituted with one or more of the following: 1) Ci -4 alkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR 6

R

7 C) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO, f) -S(O)mR 6 a, or g) -C(O)NR 6

R

7 2) aryl or heterocycle, 3) halogen, 4) OR 6

NR

6

R

7 6) CN, 7) N02, 8) CF3; 9) -S(O)mR 6 a,

-C(O)NR

6

R

7 or 11) C3-C6 cycloalkyl; M is 0, 1 or 2; n is 0, 1, 2, 3or 4; p is 0,1, 2, 3or 4; q is Ilor 2; WO 97/38665 WO 9738665PCTJUS97/06487 -13 r is 0 to 5, provided that r is 0 when V is hydrogen; s is 0Oorl1; t is 0Oorl1; u is 4 or 5; and v is 0, 1or 2; or a pharmaceutically acceptable salt thereof.

In a second embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula B:

(R

9 )q RR )2 V Al(CRla 2 (CRlaOn W -C tx

RH

4 R

B

wherein: Ri1a and Ri1b are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CI0 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, R 1 0

R

1 1 RIOC(O)NRIO-, (RIO 0 )2N- CN, N02, (RIO)2N-C(NRIO)-, RIOC(O)-, N3, -N(IO2,or RI I0C(O)NRIO-, c) unsubstituted or substituted Cl -C6 alkyl wherein the substitutent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-CI 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RIO0-, R I IS R I 0 C(O)NR 1 (R 10

CN,

(R]

0 )2N.-C(NRIO)-, RIOC(O)-, N3, -N(RIO)2, and Ri 1 0OC(O)-NR10-; WO 97/38665 PCT/US97/06487 14- Ric is selected from: a) hydrogen, b) unsubstituted or substituted Ci-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 00-,

R

1 1 R10C(O)NR 10 (R10)2N-C(O)-, CN,

(R

10 )2N-C(NR10)-, RIOC(O)-, R 10 N3, -N(R10)2, and R 1 1

OC(O)-NR

10 and c) unsubstituted or substituted aryl;

R

2 and R 3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or

R

6 R or R 6 substituted heterocycle, OR 10 O O wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C1-4 alkyl, b) (CH2)pOR 6 c) (CH2)pNR 6

R

7 d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C1-4 alkyl, h) SR 6 a, S(O)R 6 a, SO2R 6 a, 2) C3-6 cycloalkyl, 3) OR 6 4) SR 6 a, S(O)R 6 a, or SO2R 6 a, WO 97138665 WO 9738665PCTJLUS97/06487 15 -NR 6 R 7 -N yR 7 0 NR 7 R 7 a 8) -O NR 6 R 7 0 9) -O OR 6 0 NR 6 R 7 0 11) -S0 2 -NR 6 R 7 R 6 12)

~N-SO

2 -R 6 a 13)R6 0 14) OR 6 0

N

3 16) F, or perfluoro-0 1 4 -alkyl; or WO 97/38665 PCT/US97/06487 16-

R

2 and R 3 are attached to the same C atom and are combined to form (CH2)u wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(CORIO)-

R

4 and R 5 are independently selected from H and CH3; and any two of R 2

R

3

R

4 and R 5 are optionally attached to the same carbon atom;

R

6

R

7 and R 7 a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) unsubstituted aryl, substituted aryl, unsubstituted heteroaryl or substituted heterocycle, c) halogen, d) HO, e)

R

0 f) -SO2R or g) N(R 10 or

R

6 and R 7 may be joined in a ring;

R

7 and R 7 a may be joined in a ring;

R

6 a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, WO 97/38665 WO 9738665PCTIUS97/06487 17 e)

YR

0 f) -S0 2 R" or g) N(R 1 0 )2;

R

8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-Cl10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 RIIS(O)m-, RIOC(O)NRIO-, (R 1 0

R

10 2N-C(NR CN, N02, R IOC(O)-, N3, -N(R 10 or R I IOC(O)NR 10-, and C) ClI -C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3 -CI 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 0-,

R

11 RIOC(O)NH-, (RI R 1 0 2N- CN, RIOC(O)-, N3, -N(R 1 0 or RIO0C(0)NH-;

R

9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RIIS(O)rn-, RIOC(O)NRIO-, (R 1 0 )2NC(O)-, R1 0 2N-C(NRIO)-, CN, N02, RlOC(O)-, N3, -N(Rto)2, or R 11OC(O)NR 1 and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(O)NRIO-, (RlO)2NC(O)-, R 1 0 2N-C(NRIO)-, CN, R lOC(O)-, N3, 102,or R I IOC (O)NR 10

R

10 is independently selected from hydrogen, Cl-C 14 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl; WO 97/38665 PCT/US97/06487 -18-

R

1 1 is independently selected from C1-C6 alkyl and substituted or unsubstituted aryl;

A

1 and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR1O-, -NRO1C(O)-, 0, -S(0)2N(R10)-, -N(R 10 or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle;

X

2 is a bond, -CH2-, -NR 6

-C(=O)NR

6

-NR

6 -0or Z is an unsubstituted or substituted group selected from aryl and heterocycle, wherein the substituted group is substituted with one or more of the following: 1) C1-4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6

R

7 2) aryl or heterocycle, WO 97/38665 PCT/US97/06487 19- 3) 4) 6) 7) 8) 9) 11) halogen,

OR

6

NR

6

R

7

CN,

N02, CF3; -S(O)mR 6 a,

-C(O)NR

6

R

7 or C3-C6 cycloalkyl; m is n is p is q is r is s is t is u is v is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; 1 or 2; 0 to 5, provided 0 or 1; 0 or 1; 4 or 5; and 0, 1 or 2; that r is 0 when V is hydrogen; or a pharmaceutically acceptable salt thereof.

A preferred embodiment of the compounds of this invention is illustrated by the following formula A:

(R

8 )r(R 9 V-A'(CRa 2 )nA 2 (CR1a 2 W

'Y

X'(C

Z

R

4

R

wherein: WO 97/38665 WO 9738665PCTIUJS97/06487 20 R I a is independently selected from: hydrogen or C I -C6 alkyl; R lb is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 -N(R 10)2 or C2-C6 alkenyl, c) unsubstituted or substituted ClI -C6 alkyl wherein the substitutent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R 1 0 0- and -N(R 10 )2; RI c is selected from: a) hydrogen, b) unsubstituted or substituted C I -C6 alkyl wherein the substitutent on the substituted CI -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RIO0-,

R

1 1 RIOC(O)NRIO-, (R 1 0

CN,

(R

1 0 RIOC(O)-, Rl 0 N3, -N(R 10 and R I I0C(O)-NR 1 and c) unsubstituted or substituted aryl;

R

3

R

4 and R 5 are independently selected from H and CH3;

R

2 is~ Ho OR 10 0 nr Ci Q11-, I k 1 1 branched, 5 _3 ~41Y 1, JL ICL1 1 U J unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 4) SR 6 a, SO2R 6 a, or NR 6 R 7 0 WO 97/38665 WO 9738665PCT/US97/06487 21 and any two of R 2

R

3

R

4 and R 5 are optionally attached to the same carbon atom;

R

6

R

7 and R 7 a are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) C 1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

R

6 a is selected from: C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) C 1 -4 alkoxy, b) halogen, or c) aryl or heterocycle; R8 is independently selected from: a) hydrogen, b) ClI-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I-C6 perfluoroalkyl, F, Cl, R 1 0 R IOC(O)NR 10-, CN, N02, (RI O)2N-C(NRIO0>, R 1 -N(Rl 0)2, or R I IOC(O)NR 10-, and c) ClI-C6 alkyl substituted by C I -C6 perfluoroalkyl, R 1 0 0-, RIOC(O)NRI (Rl 0 )2N-C(NRIO)-, RIOC(O)-, 102,or R I IOC (O)NR

R

9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R 1 0 RI IS R IOC(O)NR 10-, CN, N02, (Rl 0 )2N-C(NRIO0>, RI 0 -N(Rl 0)2, or R1 1 OC(O)NR 10-, and WO 97/38665 PCT/US97/06487 -22c) C1-C6 alkyl unsubstituted or substituted by C -C6 perfluoroalkyl, F, Cl, R 10

R

1 1

R

10 CN, (R 10 )2N-C(NR10)-, R10C(O)-, -N(R10)2, or R110C(O)NR10-;

R

10 is independently selected from hydrogen, C1-C14 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl;

R

11 is independently selected from C1-C6 alkyl and substituted or unsubstituted aryl;

R

12 is selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted alkyl, suvbstituted aryl or substituted heterocycle is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C1-4 alkyl, b) (CH2)pOR 6 c) (CH2)pNR 6

R

7 d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C1-4 alkyl, h) SR 6 a, S(O)R 6 a, SO2R 6 a, 2) C3-6 cycloalkyl, 3) OR 6 4) SR 6 a, S(O)R 6 a, or SO2R 6 a, WO 97/38665 WO 9738665PCT/US97/06487 23 -NR 6 R 7

R

6 6) -N yR 7 0 7) 77 N yNR Ra 0 8) fy NR 6 R 7 0 9) -0O OR 6 0 "yNR 6 R 7 0 11) -S0 2 -NR 6 R 7 R 6 12) -N-SO 2 -R 6 a WO 97/38665 WO 9738665PCTIUS97/06487 24 13)R6 0 14) YO6 0

N

3 16)

F,

17) perfluoro-0 1 4 -alkyl, or 18) C 1 6 -alkyl;

A

1 I and A 2 are independently selected from: a bond, -CH=CH-, -CE=C-, -C(0)NRIO-, -NRIOC(O)-, 0, or S(O)m; is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) ClI-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A] is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X is -CH2- or WO 97/38665 WO 9738665PCTIUS97/06487 25 X I is a bond, -NR 6

-NR

6 or Y is selected from: a) hydrogen, b) R 10 R I IS(O)m-, R I C(O)NR 10-, (R I 0

CN,

N02, (RIO)2N-C(NRIO)-,

R

1 2 RIO0C(O)-, N3, F, 102,or R 1 0C (O)NR 1 and c) unsubstituted or substituted C I -C6 alkyl wherein the substitutent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, RIO0-, RIOC(O)NRIO-,

(R

1 0 RIOC(O)- and RIO0C(O)-; Z is an unsubstituted or substituted group selected from aryl and heterocycle, wherein the substituted group is substituted with one or more of the following: 1) C1-4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6

R

7 2) aryl or heterocycle, 3) halogen, 4) OR 6

NR

6

R

7 6) CN, 7) N02, 8) CF3; 9) -S(O)mR 6 a,

-C(O)NR

6

R

7 or 11) C3-C6 cycloalkyl; WO 97/38665 PCT/US97/06487 -26m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; pis 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 0 or 1; t is 1; and v is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

In a another preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula

B:

(R

9 )q R 2 V A(CRla 2 n

A

2 (CRa 2 W (CR b 2 )p N-(CRC 2 tt x 2

R

4

R

B

wherein: R a is independently selected from: hydrogen or C1-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R1 0

-N(R

10 )2 or C2-C6 alkenyl, c) unsubstituted or substituted Ci-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from WO 97/38665 PCT/US97/06487 -27unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R 10 0- and -N(R10)2; Rlc is selected from: a) hydrogen, b) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R11S(O)m-, R 10 C(O)NR10-, (R10)2N-C(O)-, CN,

(R

10 )2N-C(NR10)-, R10C(O)-, R 10 N3, -N(R10)2, and R 1 1 OC(O)-NR1O-, and c) unsubstituted or substituted aryl;

R

3

R

4 and R 5 are independently selected from H and CH3;

NR

6

R

7

R

2 is H; O or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 4) SR 6 a, SO2R 6 a, or

NR

6

R

7 and any two of R 2

R

3

R

4 and R 5 are optionally attached to the same carbon atom;

R

6

R

7 and R 7 a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle; WO 97/38665 WO 9738665PCTIUS97/06487 28

R

6 a is selected from: C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) CI-4 alkoxy, b) halogen, or c) aryl or heterocycle;

R

8 is independently selected from: a) hydrogen, b) Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RIO0-, R1OC(O)NRIO-, CN, N02, (RIO)2N-C(NR 1

R

1 0 -N(Rl 0)2, or R I I0C(O)NR 10-, and c) C I-C6 alkyl substituted by ClI-C6 perfluoroalkyl, R 1 0 0-, RIOC(O)NRIO-, (R 1 0 )2N-C(NR 1

R

1

OC(O)-,

102,or R 1 1 0OC(O)NR 1 0-

R

9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R 1 0 R I 1 S(O)rn-, R I C(O)NR 1 CN, N02, (RIO)2N-C(NR 1 R 1 0

-N(R

1 0)2, or R I IOC(O)NR1-, and c) C I -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Cl, RIO0-, RIIS(O)m-, RIOC(O)NRI 0 CN, (R 1 0 )2N-C(NRlO)-, RIOC(O)-, -N(RIO)2, or R I IOC(O)NR RIO is independently selected from hydrogen, Cj -C 14 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl; WO 97/38665 PCT/US97/06487 -29

R

A

1 and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR10-, -NR 1 0, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;

X

2 is a bond, -CH2-, -NR 6 -C(=0)NR 6

-NR

6 -0or Z is an unsubstituted or substituted aryl wherein the substituted aryl is substituted with one or more of the following: 1) C1-4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6

R

7 c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, WO 97/38665 WO 9738665PCT/US97/06487 2) 3) 4) 6) 7) 8) 9) 11) 30 e) HO, f) -S(O)mR 6 a, or g) -C(O)NR 6

R

7 aryl or heterocycle, halogen,

OR

6

NR

6

R

7

CN,

N02, CF3; -S (O)mR 6 a,

-C(O)NR

6

R

7 or C3-C6 cycloalkyl; m is n is p is r is s 15 t is v is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; 0 to 5, provided that r is 0 when V is hydrogen; 0 or 1; 1; and 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

A further preferred embodiment of the compounds of this invention are illustrated by the formula C: (R )r R9 V- A1(C R 2 )fA (C R 2 n-N (C~b 2 )~Xl-(CRlo4k-

Z

wherein: WO 97/38665 PCT/US97/06487 -31 Ra is selected from: hydrogen or C1-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 -N(R10)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R 10 or -N(R10)2; Ric is selected from: a) hydrogen, b) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0 0-, RllS(O)m-, R10OC(O)NR 10 (R10)2N-C(O)-, CN, (R10)2N-C(NR10)-, R10C(O)-, R 10 N3,

-N(R

10 and R 1 1

OC(O)-NR

10 and c) unsubstituted or substituted aryl;

R

3 and R 4 independently selected from H and CH3;

NR

6

R

7

R

2 is selected from H; OR10; O or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 4) SR 6 a, SO2R 6 a, or

NR

6

R

7 0 WO 97/38665 PCT/US97/06487 -32and R 2

R

3 and R 4 are optionally attached to the same carbon atom;

R

6 and R 7 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

R

6 a is selected from: Cl-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

R

8 is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 RO1C(O)NR 10 CN, N02,

(R

10 )2N-C(NRIO)-, R 10 -N(R10)2, or

R

1 1

OC(O)NR

10 and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 0-, RO1C(O)NRIO-, (R 10 )2N-C(NR 10 R1OC(O)-, -N(R10)2, or R 1 1

OC(O)NR

10

R

9 a is hydrogen or methyl;

R

10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;

R

1 1 is independently selected from C1-C6 alkyl and aryl; WO 97/38665 WO 9738665PCT/US97/06487 33

R

12 is selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted alkyl, substituted aryl or substituted heterocycle is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) CI1-4 alkyl, b) (CH2)pOR 6 c) (CH2)pNR 6

R

7 d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C 1-.4 alkyl, h) SR 6 a, S(O)R 6 a, SO2R 6 a, 2) C3-6 cycloalkyl, 3) OR 6 4) SR 6 a, S(O)R 6 a, or SO2R 6 a, -NR 6 R 7 6) -N 0 7) 77 -N YNR Ra 0 WO 97/38665 WO 9738665PCTIUS97/06487 34 8) -0 NR 6 R 7 0 9) -0 OR 6 0 "Y N 0 11) -S0 2 -NR 6 R 7 12) -NS2 R6 13)R6 0 14) -rOR 6 0

N

3 16)

F,

17) perfluoro-C..

4 -alkyl, or 18) 0 1 6 -alkyl;

A

1 I and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NRIO-, -NRIOC(0)-, 0, or S(O)m; V is selected from: a) hydrogen, WO 97/38665 WO 9738665PCT/US97/06487 35 b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; X is -CH2- or XI is a bond,

-NR

6

-NR

6 or Y is selected from: a) hydrogen, b) R 1 0 RI IS R I C(O)NR 1 (R 1 02N-C(O)-, CN, N02, (Rlo)2N-C(NRIO)-,

RI

2 RIO0C(O)-, N3, F, -N(R 10 or R IIOC(0)NR 10- c) unsubstituted or substituted C I -C6 alkyl wherein the substitutent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, R 1 0

RIOC(O)NRIO-,

(RIO)2N-C(O)-, Rl 0 and RIO0C(O)-; Z is an unsubstituted or substituted aryl, wherein the substituted aryl is substituted with one or more of the following: 1) Ci-4 alkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR 6

R

7 c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO, f)J S(O)mR 6 a, or WO 97/38665 WO 9738665PCTIUS97/06487 2) 3) 4) 6) 7) 8) 9) 11) 36 g) -C(O)NR 6

R

7 aryl or heterocycle, halogen,

OR

6

NR

6

R

7

CN,

N02, CF3; -S(O)mR 6 a,

-C(O)NR

6

R

7 or C3-C6 cycloalkyl; mnis n is p is r is v is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; and 0 to 5, provided that r is 0 when V is hydrogen; and 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

Another further preferred embodiment of the compounds of this invention are illustrated by the formula D: (R 8 )r R9 V -OAla 2 )A (CRla 2 Ny -kN- (GR'c 2 Z 31b 2p -R2 4 wherein: Ria is selected from: hydrogen or Cl-C6 alkyl; Rlb is independently selected from: WO 97/38665 PCT/US97/06487 37 a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 1 0 -N(R10) 2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, Rl00-, or -N(R10)2; Ric is selected from: a) hydrogen, b) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-,

R

1 1

R

10 C(O)NR1O-, (R 10

CN,

(R

10 )2N-C(NR10)-,

R

10 R1OOC(O)-, N3,

-N(R

10 and R 1 1 0C(O)-NR 1 0 and c) unsubstituted or substituted aryl;

R

3 and R 4 independently selected from H and CH3;

NR

6

R

7

R

2 is selected from H; OR10; O or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 4) SR 6 a, SO2R6a, or

NR

6

R

7

O

and R 2

R

3 and R 4 are optionally attached to the same carbon atom;

R

6 and R 7 are independently selected from: WO 97/38665 PCTIUS97/06487 38 H; Cp.4 alkyl, C3-.6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) C 1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

R

6 a is selected from: CI-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

R

8 is independently selected from: a) hydrogen, b) C1I-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1I-C6 perfluoroalkyl, F, Cl, RIO0-, RIOC(O)NR 1 CN, N02, (RIO)2N-C(NRl RIOC(O)-, -N(RIO)2, or R1 1 OC(O)NR 10-, and c) C1I-C6 alkyl substituted by C I-C6 perfinoroalkyl, R 1 0 0-, RIOC(O)NR 10., (R 10 )2N-C(NRI10>, RI OC(O)-, -N(R 10)2, or R I I0C(O)NR

R

9 a is hydrogen or methyl; *R16 is independently selected from hydrogen, C I -C 14 alkyl, substituted or unsubstituted benzyi and substituted or unsubstituted aryl; R I is independently selected from C 1 -C6 alkyl and substituted or unsubstituted aryl; A'I and A 2 are independently selected from: a bond, -CH=CH-, -CEC-, WO 97/38665 PCT/US97/06487 39 -C(O)NRO1-, -NR1OC(O)-, O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) Ci-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m;

X

2 is a bond, -CH2-, -NR 6 -C(=0)NR 6

-NR

6 -0or Zis an unsubstituted or substituted aryl, wherein the substituted aryl is substituted with one or more of the following: 1) C1-4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6

R

7 2) aryl or heterocycle, 3) halogen, 4) OR 6

NR

6

R

7 6) CN, WO 97/38665 PCT/US97/06487 7) 8) 9) 11) N02, CF3; -S(O)mR 6 a,

-C(O)NR

6

R

7 or C3-C6 cycloalkyl; m is n is p is ris v is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; and 0 to 5, provided that r is 0 when V is hydrogen; and 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

In another embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula E:

H

XN

R

2

R

3 SN N Si (CRb 2 X X'-(CRC 2

-Z

d \J R4

R

8

E

wherein: Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 -N(R10)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R 1 0 or -N(R10)2; WO 97/38665 PCT/US97/06487 -41- Rlc is selected from: a) hydrogen, b) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0 0-,

R

1 1

R

10

C(O)NR

10

(R

10

CN,

(R10)2N-C(NR10)-, R10C(O)-,

R

1 OOC(O)-, N3, -N(R10)2, and R 1 1

OC(O)-NR

10 and c) unsubstituted or substituted aryl;

R

3 and R 4 independently selected from H and CH3; SN R 6

R

7

R

2 is selected from H; OR 10 O or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 4) SR 6 a, SO2R 6 a, or

NR

6

R

7 0 and R 2

R

3 and R 4 are optionally attached to the same carbon atom;

R

6

R

7 and R7a are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

R

6 a is selected from: WO 97/38665 PCT/US97/06487 -42- C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

R

8 is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CI-C6 perfluoroalkyl, F, Cl, R 1 0

R

10 C(O)NR10-, CN, NO2,

(R

10 )2N-C(NR10)-, R10C(O)-, -N(R10)2, or

R

1 1 0C(O)NR10-, and c) C1-C6 alkyl substituted by CI-C6 perfluoroalkyl, R 10 0-, R1 0 C(O)NR10-,

(R

10 )2N-C(NR10)-,

R

10

-N(R

10 or R 1 1

OC(O)NR

10

R

10 is independently selected from hydrogen, CI-C14 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl;

R

12 is selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted alkyl, suvbstituted aryl or substituted heterocycle is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C1-4 alkyl, b) halogen, c) CN, d) perfluoro-C1-4 alkyl, 2) C3-6 cycloalkyl, 3) OR 6 WO 97/38665 WO 9738665PCTIUS97/06487 43 4) SR 6 a, S(O)R 6 a, Or SO2R 6 a, -rR 0 6) -rOR 6 0 7)

N

3 8)

F,

9) perfluoro-C 1 4 -alkyl, or Cl 1 6 -alkyl; X is -CH2- or X I is a bond, or Y is selected from: a) hydrogen, b) R 1 0 RI IS(O)m-, R IOC(O)NR 10

CN,

N02, (Rl 0 )2N-C(NRIO)-, R 12

R

10 N3, F, -N(R 10 or R I IOC(O)NR unsubstituted or substituted C I -C6 alkyl wherein the substitutent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, R 1 0

RIOC(O)NRIO-,

(R

1 0 RIOC(O)- and RIO0C(O)-; Z is an unsubstituted or substituted aryl, wherein the substituted aryl is substituted with one or more of the following: 1) CI-.4 alkyl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) NR 6

R

7 WO 97/38665 WO 9738665PCT/US97/06487 -44- 2) 3) 4) 6) 7) 8) 9) 11) c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO, f) -S(O)mR 6 a, or g) -C(O)NR 6

R

7 aryl or heterocycle, halogen,

OR

6

NR

6

R

7

CN,

N02, CF3; -S (O)mR 6 a,

-C(O)NR

6

R

7 or C3-C6 cycloalkyl; in is p is v is 1 or 2; 1, 2, 3 or 4; and 1 or 2; or a pharmaceutically acceptable salt thereof.

In another embodiment of this invention, the inhibitors of farnesyl -protein transferase are illustrated by the formula F: R 2 R 3 (CR' C 2)

Z

wherein: WO 97/38665 PCT/US97/06487 Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl,

R

10 -N(R10) 2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R100-, or

-N(R

1 0 )2; Rc is selected from: a) hydrogen, b) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0 0-, R11S(O)m-, R10C(O)NRIO-,

(R

10

CN,

(R

10 )2N-C(NR10)-,

R

1

R

10 N3,

-N(R

10 and R11OC(O)-NR10-, and c) unsubstituted or substituted aryl;

R

3 and R 4 independently selected from H and CH3;

SNR

6

R

7

R

2 is selected from H; ORIO; O or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 4) SR 6 a, SO2R 6 a, or N R 6

R

7

R

and R 2

R

3 and R 4 are optionally attached to the same carbon atom; WO 97/38665 WO 9738665PCTIUS97/06487 46

R

6

R

7 and R 7 a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl., aryl, heterocycle, unsubstituted or substituted with: a) C 1 -4 alkoxy, b) halogen, or c) aryl or heterocycle;

R

6 a is selected from: Cl-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Ci 1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

R

8 is independently selected from: a) hydrogen, b) C 1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1I-C6 perfluoroalkyl, F, Cl, RIO0-, RIOC(O)NRIO-, CN, N02, (R 10 )2N-C(NR R IOC(O)-, R I OOC(O)-, -N(R 10)2, or R I I0C(O)NR 1 and c) C I-C6 alkyl substituted by C1I-C6 perfluoroalkyl, R 1 0 0-, RlOC(O)NR 10., (R 1 0 )2N-C(NRl RlOC(O)-, RIO0C(O)-, or RI 1OC(O)NRIO-; R 1 0 is independently selected from hydrogen, Cl1-C 14 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl;

R

1 I is independently selected from C I -C6 alkyl and substituted or unsubstituted aryl;

X

2 is -CH2-,

-C(=O)NR

6 or -R- WO 97/38665 WO 9738665PCTIUS97/06487 47 Z is an unsubstituted or substituted aryl, wherein the substituted aryl is substituted with one or more of the following: 1) Ci -4 alkyl, unsubstituted or substituted with: a) C 1 -4 alkoxy, b) NR 6

R

7 2) aryl or heterocycle, 3) halogen, 4) OR 6

NR

6

R

7 6) CN, 7) N02, 8) CF3; 9) -S(O)mR 6 a,

-C(O)NR

6

R

7 or 11) C3-C6 cycloalkyl.; m is 0,l1or 2; p is 0,1, 2, 3or 4;and v is 0, 1 or 2; or the pharmaceutically acceptable salts thereof.

The preferred compounds of this invention are as follows: N-1{ (4-Cyanobenzyl)-l1H-imidazol-5 -ylj methyl -4-(3-methylphenyl)- 4-hydroxy piperidine, N- I 1-(4-Cyanobenzyl)- 1 H-imidazol-5-yl] methyl I -4-(3-chlorophenyl)-4 hydroxy piperidine, WO 97/38665 WO 9738665PCT/1JS97/06487 -48- N-1 (4-Cyanobenzyl)- 1H-imidazol-5-yl] methyl methylbenzyl)isonipecotic acid methyl ester, N- [1 -(4-Cyanobenzyl)- 1H-imidazol-5-yl]methyl 1-4- (3 -methylphenyl)-4 hydroxy piperidine, N- -(4-Cyanobenzyl)-lIH-imidazol-5-yl]acetyl methylbenzyl)isonipecotic acid methyl ester, N- -(4-Cyanobenzyl)- 1H-imidazol-5-yl]acetyl 14(4 methylbenzyl))isonipecotic acid methyl ester, N- -(4-Cyanobenzyl)- 1H-imidazol-5-yl] acetyl methylbenzyl))isonipecotic acid methyl ester, N- [11-(4-Cyanobenzyl)- 1H-imidazol-5-yl]acetyl I-(,4 dichlorobenzyl))isonipecotic acid methyl ester, N- -(4-Cyanobenzyl)-l1H-imidazol-5-yl]acetyl methoxybenzyl)isonipecotic acid methyl ester, N-1{ (4-Cyanobenzyl)- 1H-imidazol-5 -yl] acetyl)}-4-( 1naphthylmethyl)isonipecotic acid methyl ester, N-1{ [1 -(4-Cyanobenzyl)- 1H-imidazol-5-yllacetyl I4(4 chlorobenzyl)isonipecotic acid methyl ester, N-1{ [1 -(4-Cyanobenzyl)-l1H-imidazol-5-yllacetyl dichlorobenzyl)isonipecotic acid methyl ester, N- {11-(4 Cyanobenzyl)- I H-imidazol-5-yl-aminocarbonyl I methylbenzyl) isonipecotic acid methyl ester, WO 97/38665 WO 9738665PCT/US97/06487 49 2(R,S)-N -(4-Cyanobenzyl)- IH-imidazol-5-yl]2-(4-.

cyanobenzyl) I acetyl- 4 2 -methylbenzyl)-isonipecotic acid methyl ester, N-f 1l-(Naphth-2-ylmethyl)- lH-imidazol-5-yl]acetyl methylbenzyl)isonipecotic acid methyl ester, N- -(4-Cyanobenzyl)- 1H-imidazol-5-yllmethyl 4 -methoxymethyl-4- (2-methylbenzyl) piperidine, N-1{ [1 -(4-Cyanobenzyl)- 1H-imidazol-5-yl] acetyl I-- 4 -methoxymethyl-4- (2-methylbenzyl) piperidine, N-f 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl]acetyl I -4-hydroxymethyl-4- (2-methylbenzyl) piperidine, N-1{ [1 -(4-Cyanobenzyl)-I--imidazol-5-yl]ethyl methylbenzyl)isonipecotic acid methyl ester, N- I [1I -(4-Cyanobenzyl)- 1 H-imidazol-5-yllmethyl I -trans-4-(3methylphenyl)-3-hydroxypiperidine, N- f I -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]methyl I -trans-4- (3methylphenyl)-3 methoxy piperidine, N- -(4-cyanobenzyl)- 1H-imidazol-5-yl]methyl -trans-4- (3methylphenyl)-3 benzyloxy piperidine, 1 2 (RS)-Amino-3-(2-tetradecyloxyphenyl)propyl-4-(2methylbenzyl)isonipecotic acid methyl ester, N-2- (S)-aminolauroyl-4- (1-napthylmethyl) isonipecotic acid methyl ester, WO 97/38665 WO 9738665PCTIUS97/06487 50 4-(Benzoxazolidin-2-one- Il-yl)- I- [1 imidazolylacetyljpiperidine, 1,2-Dihydro-4(H)-3, 1 -benzoxazin-2-one- I 1-[I1 4 -cyanobenzyly- 4-(1I,2-Dihydro-4(H)-3, I -benzoxazin-2-one- Il-yl)-l 1-[I1 -(4-cyanobenzyl)> -imidazolylmethyllpiperidine, N- [2-f (4-Cyanobenzyl)-5-imidazolyl ethyl]-4-carbamoyl- 1 phenylpiperi dine 4- [2-11- (4-Cyanobenzyl)-5-imidazolyl I ethyl]- -1 -phenylpiperidine 4- f 5 4 -Hydroxymethyl-4-(3-trifluoromethoxybenzyl)ypiperidine- I 1ylmethyl] imidazol- 1 -ylmethyl benzonitrile 4-15- [4-Hydroxymethyl-4- (3 -trifluoromethoxybenzyl)-piperidine- 1 ylmethyl]-2-methylimidazol- 1 -ylmelihyl I benzonitrile 4- f5- 4 -Hydroxymethyl-4-(3 -trifluororethylbenzylypiperidineylmethyllimidazol- 1 -ylmethyl I benzonitrile 4-1 5- [4-Hydroxymethyl-4-(3 -trifluoromethylbenzyl)-piperidine 1ylmethyl] -2-methylimidazol- 1 -ylmethyl I benzonitrile 4-15 4 -Hydroxymethyl-4-(2-trifluoromethylbenzyl).piperidine 1ylmethyllimidazol- 1 -ylmethyl I benzonitrile 4-15- 4 -Hydroxymethyl-4-(2-methylbenzyl)piperidine-I 1ylmethyl]imidazol- 1 -ylmethyl I}benzonitrile 4-1f5- 4 -Hydroxymethy1-4-(3-methylbenzy)piperidine- I 1ylmethyl]irnidazol- 1 -ylmethyl I}benzonitrile WO 97/38665 WO 9738665PCTIUS97/06487 51 4- [4-Hydroxymethyl-4-(3 -methylbenzy)piperidine-. I -ylmethyl] -2methylimidazol- 1 -ylmethyl I benzonitrile 4- 1 2- [4-Hydroxymethyl-4-(3 -methylbenzyl)piperidine-. l-yl]-2oxoethyl I imidazol- 1 -ylmethyl)benzonitrile 4-1{5- [4-Hydroxymethyl-4- (3 -methylbenzyl)piperidine- 1 carbonyl] imidazol- 1 -ylmethyl I}benzonitrile 4-1{ 4 -Hydroxymethyl-4-(2-methylbenzyl)piperidine- I 1carbonyllimidazol- I -ylmethyl) benzonitrile 4-1{5- [4-Hydroxymethyl-4- (3 -chlorobenzyl)-piperidine- 1 -ylmethyl] 2-methylimidazol- 1 -ylmethyl I benzonitrile 4-1{5- [4-Hydroxyrnethyl-4- 2 -cyanobenzyl)-piperidine- 1 -ylmethyl] -2methylimidazol- 1 -ylmethyl I benzonitrile 4-1{5- [4-Hydroxymethyl-4- (3 -cyanobenzyl)-piperidine- 1 -ylmethyl] -2methylimidazol- 1 -yl methyl I}benzonitrile 4- 1 5- 4 -Hydroxymethyl-4-(4-cyanobenzyl)piperidine- 1 -ylmethyl] -2methylimidazol- 1 -ylmethyl I benzonitrile 4- 4 -Hydroxymethyl-4-(2,5-dimethylbenzyl)piperidine- I 1ylmethyl] -2-methylimidazol- 1 -ylmethyl I benzonitrile 4-1{5- r 4 -Hydroxymethyl -4-(2,5-dichlorobenzyl)piperidine- 1ylmethyll-2-methylimidazol- I -ylmethyl I benzonitrile 4-1{5- [4-Jlydroxymethyl-4- (3,5 -dimethylbenzy1)piperidine- I ylmethyl] -2-methylimidazol- 1 -ylmethyl benzonitrile 4-(5-1{4-Hydroxymethyl-4- [3 piperidine- 1 -ylmethyl 2 -methylimidazol- 1 -ylmethyl)benzonitrile WO 97/38665 WO 9738665PCTIUS97/06487 52 4-1{5- [4-Hydroxymethyl-4-(2 ,3 -dichlorobenzyl)piperidine 1ylmethyl]-2-methylimidazol- 1-ylmethyIl }benzonitrile 4- [5-(4-Hydroxymethy-4-benzylpiperidine-. 1 -ylmethyl)-2methylimidazol- 1 -ylmethyllbenzonitrile 4-1{5- [4-Hydroxymethyl-4- 3 -trifluoromethoxybenzyl).piperidine. 1 ylmethyl]-2-methylimidazol- 1 -ylmethyl lbenzamide 4-1{5- 4 -Methoxymethyl-4-(3-methylbenzyl)-piperidine- I 1ylmethyl] imidazol- 1 -ylmethyl I benzonitrile 4-1{5- 4 -Methoxymethyl-4-(3-methylbenzyl)-pipeidine- 1 -ylmethyl]- 2-methylimidazol- 1 -ylmethyl I benzoni trile 4-1{5- [4-Methoxymethyl-4-(3 -trifluoromethoxybenzyl)-piperidine 1ylmethyllimidazol- 1 -ylmethyl lbenzonitrile 4-f{ 5- [4-Methoxymethyl-4- (3 -trifluoronethoxybenzyl)-pperdine..1ylmethyl]-2-methylimidazol -1 -ylmethyl I benzonitrile 4- 4 -Methoxymethyl-4-(2-trifluoromethoxybenzylpperidine 1ylmethyllimidazol- 1 -ylmethyl I}benzonitrile 4- 4 -Methoxymethyl-4-(2-trifluoromethoxybenzyl).piperidine 1ylmethyl]-2-methylimidazol- I -ylmethyl benzonitrile 4-1{5- [4-Methoxymethyl-4-(3 -cyanobenzyl)-piperidine- 1 -ylmethyl] -2methylimidazol-1I-ylmethyl I}benzonitrile 4-(5-1{ 2 4 -Methoxymethyl-4-(3-methylbenzyl)-piperidine- I -yl]-2oxoethyl imidazol- 1 -ylmethyl)benzonitrile 4-{f 5- [4-Methoxymethyl-4-(3 -methylbenzyl)piperidine- I carbonyl]limidazol- 1 -ylmethyl I}benzonitrile WO 97/38665 WO 9738665PCT[US97/06487 53 Methyl 1- [3 -(4-cyanobenzyl)-3H-imidazol-4-ylmethyl] (3methylbenzyl)piperidine-4-carboxylate Methyl 1- [3 -(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-(3trifluoromethoxybenzyl)piperidine-4-carboxylate Methyl 1- [3 -(4-cyanobenzyl)-2-methyl-3H-imidazol-4-ylmethyl] -4- (3-trifluoromethoxybenzyl)piperidine-4-carboxylate Methyl 1- [3 -(4-cyanobenzyl)- 3H-imidazol-4-ylmethyl]-4-(2trifluoromethoxybenzyl)piperidine-4-carboxylate Methyl 1- [3-(4-cyanobenzyl)- 3H-imidazol-4-ylmethyl] cyanobenzyl)piperidine-4-carboxylate Methyl 1- (4-cyanobenzyl)-3H-irnidazol-4-ylmethyl] [3- (benzyloxycarbonylaminomethyl)benzyl]piperidine-4-carboxylate Methyl 1- (4-cyanobenzyl)-3H-irnidazol-4-ylmethyl] [3- (arninomethyl)benzyllpiperidine-4-carboxylate Ethyl 1- [3 -(4-cyanobenzyl)-2-rnethyl-3H-imidazol-4-ylmethyl] [3- (methanesulfonylaminomethyl)benzyl]piperidine-4-carboxylate Ethyl 1- [3 -(4-cyanobenzyl)-2-methyl-3H-imidazol-4-ylmethyl]-4-(3nitrobenzyl)piperidine-4-carboxylate Ethyl 1 (4-cyanobenzyl)-2-methyl-3H-imidazol-4-ylmethyl] (3methanesulfonylaminobenzyl)piperidine-4-carboxylate Ethyl 1- [3 -(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4benzylpiperidine-4-carboxylate Methyl 1- (4-cyanobenzyl)- 3H-imidazol-4-ylmethyl] -4cyclopropylrnethylpiperidine-4-carboxylate WO 97/38665 WO 9738665PCTIUS97/06487 54 Methyl 1- [3-(4-cyanobenzyl)- 3H-imidazol-4-ylcarbonyl]-4-(3 methylbenzyl)piperidine-4-carboxylate Methyl 1- [3-(4-cyanobenzyl)-3H-imidazol-4-ylcarbonyl] methylbenzyl)piperidine-4-carboxylate Methyl 1- (4-cyanobenzyl)-3H-imidazol-4-ylacetyl] trifluoromethoxybenzyl)piperidine-4-carboxylate Methyl 1- [3 -(4-cyanobenzyl)- 3H-imidazol-4-ylacetyl] (2trifluoromethoxybenzyl)piperidine-4-carboxylate Methyl 1- [3 -(4-cyanobenzyl)-3H-imidazol-4-ylacetyl] cyanobenzyl)piperidine-4-carboxylate Methyl 1- (4-cyanobenzyl)-3H-imidazol-4-ylethyl] (3methylbenzyl)piperidine-4-carboxylate Methyl 2- (n-butyl)-1- [3 -(4-cyanobenzyl)- 3H-imidazol-4ylmethyl]-4- (3-methylbenzyl)piperidine-4-carboxylate 1- [3-(4-Cyanobenzyl)-3 H-imidazol-4-ylrnethyl] methylbenzyl)isonipecotamide 1 -(4-Cyanobenzyl)-3H-i midazol-4-ylmethyl methylbenzyl)isonipecotamide 1- [3 -(4-Cyanobenzyl)- 3H-imidazol-4-ylacetyl] (3-methylbenzyl)isonipecotamide 1- (4-Cyanobenzyl)-3H-imidazol-4-ylacetyl] (2-methylbenzyl)isonipecotamide 1- (4-Cyanobenzyl)-3H-imidazol-4-ylcarbonyl] -4-(3-methylbenzyl)isonipecotamide WO 97/38665 WO 9738665PCTIUS97/06487 55 1- (4-Cyanobenzyl)-3H-imidazol-4-ylcarbonyl]- 4 -(2-methylbenzyl)isonipecotamide 1- (4-Cyanobenzyl)-3H-imidazol-4-ylmethyl] methylbenzyl)piperidine-4-carbonitrile 1- [3-(4-Cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-(2methylbenzyl)piperidine-4-carbonitrile 1- (4-Cyanobenzyl)-3 H-imidazol-4-ylmethyl] methylbenzyl)piperidine-4-carbonitrile 1- [3-(4-Cyanobenzyl)-2-methyl-3H-imidazol-4-ylmethyl]-4-(3 methylbenzyl)piperidine-4-carbonitrile 1- [3-(4-Cyanobenzyl)-3H-imidazol-4-ylcarbonyl] methylbenzyl)piperidine-4-carbonitrile 1- (4-Cyanobenzyl)-3H-imidazol-4-ylcarbonyl] methylbenzyl)piperidine-4-carbonitrile 1- [3 -(4-Cyanobenzyl)-3H-imidazol-4-ylacetyl] methylbenzyl )piperidine-4-carbonitrile 1- (4-Cyanobenzyl)-3H-imidazol-4-ylacetyl] (2methylbenzyl)piperidine-4-carbonitrile 1- (4-Cyanobenzyl)-3H-imidazol-4-ylethyl] methylbenzyl)piperidine-4-carbonitrile 1- (4-Cyanobenzyl)-3H-imidazol-4-ylethyl] methylbenzyl)piperidine-4-carbonitrile 4-1{5- [4-Hydroxyrnethyl-4- (4-methylpyridin-2-ylmethyl)-piperidine- 1 -ylmethyl] -2-methylimidazol-1I-ylmethyIl }benzonitrile WO 97/38665 WO 9738665PCTIUS97/06487 56 4- 1 5- 4 -Hydroxymethyl-4-(6-methylpyridin-.2ylmethyl)>piperidine- 1 -ylmethyl]-2-methylimidazol- 1 -ylmethyl benzonitrile 4- f5- [4-Hydroxymethyl-4- 2 -methylpyridin-4-ylmethyl )-piperidine- 1 -ylmethyl]-2-methylimidazol- 1 -ylmethyl) benzonitrile 4-f15-[ 4 -Hydroxymethyl-4-(4-chloropyridin..

2 -ylmethyl)-piperidine- 1 -ylmethyl]-2-methylimidazol- 1 -ylmethyl I}benzonitrile 4-1{5-[4Mtoyehl4(6mtyprdn2ylehl-ieiie 1 -ylmethyl]imidazol- 1 -ylmethyl I benzonitrile 4-15- [4-I-ydroxymethyl-4- (6-hydroxypyridin-2-ylmethyl).

piperidine- 1 -ylmethyl] -2-methylimidazol- 1 -ylmethyl I benzonitrile 4- [5 4 -Hydroxyrnethyl-4-quinolin-2..ylmethyl-piperidine 1ylmethyl)-2-methylimidazol- 1 -ylmethyl]benzonitrile Methyl 1- 3 4 -cyanobenzyl)-3H-imidazol-4-ylmethyl] methylbenzoyl)piperidine-4-carboxylate 1- 3 -(4-Cyanobenzyl)-3H-imidazol-4.ylmethylj (3methylbenzoyl)piperidine 1- 4 -Cyanobenzyl)-3H-imidazol-4.ylmethyl] (hydroxy-mtolylmethyl)piperidine 4-15- [4-Hydroxymethyl-4- (3 -tolylsulfanyl)piperidine- 1ylmethyllimidazol- 1-ylmethyl }benzonitrile 4-f 5- 4 -Methoxymethyl-4-(3-tolylsulfanyl)pipe-idine 1ylmethyllimidazol- 1 -ylmethyl I benzonitrile 4- 15 S[ 4 -Methoxymethyl-4-(3-tolylsulfinyl)piperidine 1ylmethyl]imidazol- I1-ylmethyl I}benzonitrile WO 97/38665 WO 9738665PCTIUS97/06487 57 4-1{5-[4-Methoxymethyl-4- (3 -tolylsulfonyl)piperidine- 1 ylmethyl]imidazol- 1 -ylmethyl IJbenzonitrile 1- (4-Cyanobenzyl)-3H-imidazol-4.ylmethyl] methylphenylamino)isonipecotarnide Ethyl 1- [3-(4-Cyanobenzyl)-3H-imidazol -4-ylmethyl] (3methylphenylamino)piperidine-.4-carboxylate 1- 3 4 -Cyanobenzyl)-3H-imidazov4-ylmethyl] -4-hydroxymethyl-4- 3 -methylphenylamino)piperidine 0- 1- [3 4 -Cyanobenzyl)-3H-imidazop4-ylmethyll-4.(3- 15methylphenylamino)piperidyl4methyI I carbamate 1- [3-(4-Cyanobenzyl)- 3 H-imidazol-4-ylmethyl] methylphenylamino)piperidy1-4.rethylurea 1- 3 4 -Cyanobenzyl)-3H-imidazo4ylmethyl-4-(3 methylphenylamino)piperidyl-4-.methylsulfamide 4-1{ 4 -(Hydroxydiphenylmethyl)piperidin- 1 -ylmethyl]imidazol- I ylmethyl I benzonitrile 4-f 4 -(Hydroxydiphenylmethyl)piperidine-l 1-carbonyllimidazol- 1ylmethyl I benzonitrile (Hydroxydiphenylmethyl)piperidin Il-yl] -2-oxoethyl 1- 3 Hirnidazol- 1 -ylmethyl)benzonitrile 1 -(Piperidin-4-ylmethyl)-5-(4-cyanobenzyl)imidazole 1 -Phenylpiperidin-4-ylmethyl)y5.(4-cyanobenzyl)imidazole WO 97/38665 WO 9738665PCTIUS97/06487 58 1 -(2-Methylphenyl)piperidin-4-ylmethyl)-s cyanobenzyl)imidazole 1-l (2-Chlorobenzoyl)piperidin-4-ylmethyl)-s cyanobenzyl)imidazole 1-l (3-Chlorobenzoyl)piperidin-4-ylmethyl)-5 cyanobenzyl)imidazole 1-l (3-Chlorobenzenesulfonyl)piperidin-4-ylmethyl)..s-(4cyanobenzyl)imidazole 1 -(3-Chlorobenzyl)piperidin-4-ylmethyl)-5-(4cyanobenzyl)imidazole 2- [3-(4-Cyanobenzyl)-3H-imidazol- Il-yl] (1 -phenylpiperidin-4yl)acetamide 2- [3-(4-Cyanobenzyl)-3H-irnidazol- l -yl] -N-benzyl-N-( 1phenylpiperidin-4-yl)acetamide 2- [3-(4-Cyanobenzyl)-3H-imidazol- 1 1 -phenyl~piperidin-4-yl)- N-pyridin-4-ylmethylacetamide 2- [3-(4-Cyanobenzyl)-3H-imidazol- Il-yl] -N-phenethyl-N-( 1phenylpiperidin-4-yl)acetamide 4-1{5- -Phenylpiperidin-4-ylarnino)methyl] imidazol- 1 ylmethyl }benzonitrile WO 97/38665 WO 9738665PCT[US97/06487 59 4- [B enzyl(l1-phenylpiperidin-4-yl) aminolmethyl imidazol- 1 ylmethyl)benzonitrile 4- -Phenylpiperidin-4-yl)pyridin-4ylmethylaminolmethyl I imidazol- 1 -ylmethyl)benzonitrile 4-(5-1 Phenethyl(I1-phenylpiperidin-4-yl)amino]methyl I imidazol- Iylmethyl)benzonitrile 4-1{5- (1 -Phenylpiperidin-4-ylamino)ethyl] imidazol- 1 ylmethyl I benzonitrile [Benzyl( 1 -phenylpiperidin-4-yl)ainino] ethyl I imidazol- 1 ylmethyl)benzonitrile 2- [3-(4-Cyanobenzyl)-3H-imidazol- Il-yl] -N-(4-cyanobenzyl)-N-l phenylpiperidin-4-yl)acetamide 1-B enzylpiperidin-4-yl)-2- (4-cyanobenzyl)- 3H-imidazol -4ylacetamide and 4-1{5- -Benzylpiperidin-4-ylamino)methyl]imidazol 1ylmethyl I benzonitrile or a pharmaceutically acceptable salt thereof.

Specific examples of the compounds of the invention are: N-1 [1I-(4-Cyanobenzyl)- 1H-imidazol-5 -yl] methyl (3 -methyiphenyl)- 4-hydroxy piperidine WO 97/38665 WO 9738665PCTIUS97/06487 60 NC

,CH

3 4- [4-Hydroxymethyl-4-(3-trifluoromethoxybenzyl)-piperidine- 1ylmethyllimidazol- 1 -ylmethyl I benzonitrile

NC\/

OCF

3 4-1{5- [4-Hydroxymethyl-4- (4-chi oropyridin-2-ylmethyl)-piperidine- 1 ylmethyl] -2-methylimidazol- 1 -ylmethyl I benzonitrile

OH

4-1{5- [4-Methoxymethyl-4-(3-tolylsulfanyl)piperidine- I1ylmethyllimidazol- 1-ylmethyl Ibenzonitrile trifluoroacetate salt 00H 3 NC NI N S N

OH

3 1- [3 -(4-Cyanobenzyl)-3H-imidazol-4-ylrnethyl] -4-hydroxymethyl-4-(3methylphenylamino)piperidine WO 97/38665 WO 9738665PCTIUS97/06487 61 NC\ I

N

H

CH

3 1- [3 -(4-Cyanobenzyl)-3H-imidazol-4-ylmethyl] methylphenylamino)-piperidy1-4-methylcarbamate 0

NH

2 0 4-'

OH

3 1 -Chlorobenzoyl)piperidin-4-ylmethyl)s cyanobenzyl)imidazole

NC

4-15- [(1-Benzylpiperidin-4-ylamino)methyl]imidazol- 1ylmethyl I benzonitrile WO 97/38665 PCT/US97/06487 -62- NCN N

NNH

N

or the pharmaceutically acceptable salts thereof.

The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. When any variable aryl, heterocycle, R 1

R

2 etc.) occurs more than one time in any constituent, its definition on each occurence is independent at every other occurence. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. "Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.

As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.

The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, 0, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may WO 97/38665 PCT/US97/06487 -63be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzoxazolidinonyl, benzoxazinonyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2 -oxoazepinyl, oxazolyl, 2 -oxopiperazinyl, 2-oxopiperdinyl, 2 -oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.

As used herein, "heteroaryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, 0, and S. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, and thienyl.

As used herein in the definition of R 2 and R 3 the term "the substituted group" intended to mean a substituted C1-8 alkyl, substituted WO 97/38665 PCT/US97/06487 -64- C2-8 alkenyl, substituted C2-8 alkynyl, substituted aryl or substituted heterocycle from which the substitutent(s) R 2 and R 3 are selected.

As used herein in the definition of R 6

R

7 and R 7 a, the substituted C1-8 alkyl, substituted C3-6 alkenyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle include moieties containing from 1 to 3 substitutents in addition to the point of attachment to the rest of the compound.

As used herein, when no specific substituents are set forth, the terms "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group which is substituted on a substitutable ring carbon atom with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(C1-C6 alkyl)2, N02, CN, (Cl-C6 alkyl)O-, -OH, (C1-C6 alkyl)S(O)m-, (C1-C6 alkyl)C(O)NH-, H2N-C(NH)-, (C]-C6 alkyl)C(O)-, (Cl-C6 alkyl)OC(O)-, N3,(C1-C6 alkyl)OC(O)NH-, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and C1-C20 alkyl.

When R 2 and R 3 are combined to form (CH2)u cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to: In addition, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to: WO 97/38665 PCT/US97/06487 0 o-"

O^"

,s-

/I

S

H 0 0 S7;

S

N

COR

1 0 Lines drawn into the ring systems from substituents (such as from R 2

R

3

R

4 etc.) indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.

Preferably, Ria and Rib are independently selected from: hydrogen, -N(Rl0)2, R 1C(O)NR10- or unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted phenyl, -N(R10)2, R 10 0- and RlOC(O)NRO1-. More preferably, Rla and Rib are independently selected from: hydrogen or unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted phenyl, -N(R 10

R

1 0 0- and R1OC(O)NRO 1 Preferably, R 2 is selected from: H, OR 1 0,

SR

6

R

7

OR

6 O O and an unsubstituted or substituted group, the group selected from C1-8 alkyl, C2-8 alkenyl and C2-8 alkynyl; wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C1-4 alkyl, b) (CH2)pOR 6 c) (CH2)pNR 6

R

7 d) halogen, 2) C3-6 cycloalkyl, 3) OR 6 4) SR 6 a, S(O)R 6 a, SO2R 6 a, WO 97/38665 PCTJUS97/06487 66 -NR 6 R 7 6) -Ny R 7 0 R 6 7) 77 N yNR Ra 0 8) -0o NR 6 R 7 0 9) -0 yOR 6 0 yNR 6 R 7 0 11) -S0 2 -NR 6 R 7 12) -NS R6 13) R 6 0 14) -OR 6 0

N

3 or 16) WO 97/38665 PCT/US97/06487 -67- Preferably, R3 is selected from: hydrogen and C1-C6 alkyl.

Preferably, R4 and R 5 are hydrogen.

Preferably, R6, R7 and R 7 a is selected from: hydrogen, unsubstituted or substituted Ci-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.

Preferably, R6a is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.

Preferably,

R

9 is hydrogen or methyl. Most preferably,

R

9 is hydrogen.

Preferably, R 10 is selected from H, C1-C6 alkyl and substituted and unsubstituted benzyl.

Preferably, R 12 is selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted alkyl, suvbstituted aryl or substituted heterocycle is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Cl-4 alkyl, b) halogen, c) CN, d) perfluoro-C1-4 alkyl, 2) C3-6 cycloalkyl, 3) OR 6 4) SR 6 a, S(O)R 6 a, or SO2R 6 a, WO 97/38665 PCT/US97/06487 -68- R 6 0 6)

OR

6 0 7)

N

3 8) F, 9) perfluoro-C1.

4 -alkyl, or Cl.

6 -alkyl.

Preferably, A 1 and A 2 are independently selected from: a bond, -C(O)NR10-, -NR 1 O, -N(R 10 -S(0)2N(RO1)- and- N(RIO)S(0)2-.

Preferably, V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.

Preferably, X 1 is a bond.

Preferably, X 2 is a bond, -CH2-, -NR 6 -C(=0)NR 6 or Preferably, Y is selected from hydrogen, R 1 0 0-,

R

I O C(0)NR10-, (R R 12 R100C(O)-, -N(R 10 )2, and unsubstituted or substituted C1-C6 alkyl. More preferably, Y is R100-, R 10 0C(O)- and unsubstituted or substituted C1-C6 alkyl.

Preferably, Z is selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted furanyl and unsubstituted or substituted thienyl. More preferably, Z is unsubstituted or substituted phenyl or unsubstituted or substituted naphthyl.

Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyrrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.

Preferably, n and r are independently 0, 1, or 2.

Preferably p is 1, 2 or 3.

WO 97/38665 PCTIUS97/06487 -69- Preferably s is 0.

Preferably t is 1.

Preferably, the moiety (R8)r I IR q V A'(CR a 2 )nA 2 (CRa 2 W (CR is selected from:

R

9 a R9b -N N

N

7

R

9 b and N R 9 (R CH2 (R)r CH 2 It is intended that the definition of any substituent or variable Rla, R 9 n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(R10)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.

The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, WO 97/38665 PCT/US97/06487 phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2 -acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.

The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods.

Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.

WO 97/38665 PCTIUS97/06487 -71 Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-29, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Substituents Ra and Rb, as shown in the Schemes, represent the substituents R 2

R

3

R

4 and R 5 substituent "sub" represents a suitable substitutent on the substituent

Z.

The point of attachment of such substituents to a ring is illustrative only and is not meant to be limiting.

These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes.

Synopsis of Schemes 1-29: The requisite intermediates utilized as starting material in the Schemes hereinbelow are in some cases commercially available, or can be prepared according to literature procedures. In Scheme 1, for example, a suitably substituted Boc protected isonipecotate I may be deprotonated and then treated with a suitably substituted alkylating group, such as a suitably substituted benzyl bromide, to provide the gem disubstituted intermediate III. Deprotection and reduction provides the hydroxymethyl piperidine IV which can be utilized is synthesis of compounds of the invention or which may be nitrogen-protected and methylated to give the intermediate V.

As shown in Scheme 2, the protected piperidine intermediate III can be deprotected and reductively alkylated with aldehydes such as 1-trityl- 4 -imidazolyl-carboxaldehyde or 1-trityl-4imidazolylacetaldehyde, to give products such as VI. The trityl protecting group can be removed from VI to give VII, or alternatively, VI can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole VIII.

The deprotected intermediate IIIa can also be reductively alkylated with a variety of other aldehydes, such as IX, as shown in WO 97/38665 PCT/US97/06487 -72- Scheme 3. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid (Scheme The reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide. The product X can be deprotected with trifluoroacetic acid in methylene chloride to give the final compound XI. The final product XI is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine XI can further be selectively protected to obtain XII, which can subsequently be reductively alkylated with a second aldehyde to obtain XIII. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XV can be accomplished by literature procedures.

Alternatively, the intermediate IIIa can be acylated or sulfonylated by standard techniques. The imidazole acetic acid XIX can be converted to the acetate XXI by standard procedures shown in Scheme 4, and XXI can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XXII. Hydrolysis and reaction with piperidine Illa in the presence of condensing reagents such as 1-(3dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads to acylated products such as XXIV.

An alternative synthesis of the hydroxymethyl intermediate IV and utilization of that intermediate in the synthesis of the instant compounds which incorporate the preferred imidazolyl moiety is illustrated in Scheme 4a. Scheme 4b illustrates the reductive alkylation of intermediate IV to provide a 4 -cyanobenzylimidazolyl substituted piperidine. The cyano moiety may be selectively oxidized with sodium borate to provide the corresponding amido compound of the instant invention.

Scheme 4c alternative preparation of the methyl ether intermediate V and the alkylation of V with a suitably substituted WO 97/38665 PCT/US97/06487 -73imidazolylmethyl chloride to provide the instant compound.

Preparation of the homologous l-(imidazolylethyl)piperidine is illustrated in Scheme 4d.

Specific substitution on the piperidine of the compounds of the instant invention may be accomplished as illustrated in Scheme 4e.

Thus, metal-halogen exchange coupling of a butynyl moiety to an isonicotinate, followed by hydrogenation, provides the 2 -butylpiperidine intermediate that can then undergo the reactions previously described to provide the compound of the instant invention.

Incorporation of a 4-amido moiety for Y is illustrated in Scheme 4f.

If the piperidine IIIa is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XXV in Scheme 5, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 5, The alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XXIX. In addition, the fully deprotected amino alcohol XXX can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXI (Scheme or tertiary amines.

The Boc protected amino alcohol XXVII can also be utilized to synthesize 2 -aziridinylmethylpiperidine such as XXXII (Scheme Treating XXVII with 1,1'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXII. The aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product

XXXIII.

In addition, the piperidine IIIa can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, as shown in Scheme 8, to obtain compounds such as XXXIX. When R' is an aryl group, XXXIX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XL. Alternatively, the amine WO 97/38665 PCT/US97/06487 -74protecting group in XXXIX can be removed, and O-alkylated phenolic amines such as XLI produced.

Scheme 9 illustrates the synthesis of the instant compounds wherein the moiety Z is attached directly to the piperidine ring. Thus the piperidone XLII is treated with a suitably substituted phenyl Grignard reagent to provide the gem disubstituted piperidine XLIII.

Deprotection provides the key intermediate XLIV. Intermediate XLIV may be acetylated as described above to provide the instant compound XLV (Scheme As illustrated in Scheme 11, the protected piperidine XLIII may be dehydrated and then hydroborated to provide the 3hydroxypiperidine XLVI. This compound may be deprotected and further derivatized to provide compounds of the instant invention (as shown in Scheme 12) or the hydroxyl group may be alkylated, as shown in Scheme 11, prior to deprotection and further manipulation.

The dehydration product may also be catalytically reduced to provide the des-hydroxy intermediate XLVIII, as shown in Scheme 13, which can be processed via the reactions illustrated in the previous Schemes.

Schemes 14 and 15 illustrate further chemical manipulations of the 4-carboxylic acid functionality to provide instant compounds wherein the substituent Y is an acetylamine or sulfonamide moiety.

Scheme 16 illustrates incorporation of a nitrile moiety in the 4-position of the piperdine of the compounds of formula A. Thus, the hydroxyl moiety of a suitably substituted 4-hydroxypiperidine is substituted with nitrile to provide intermediate IL, which can undergo reactions previously described in Schemes 1-8.

Scheme 17 illustrates the preparation of several pyridyl intermediates that may be utilized with the piperdine intermediates such as compound I in Scheme 1 to provide the instant compounds. Scheme 18 shows a generallized reaction sequence which utilizes such pyridyl intermediates.

WO 97/38665 PCT/US97/06487 Compounds of the instant invention wherein Xl is a carbonyl moiety may be prepared as shown in Scheme 19. Intermediate L may undergo subsequent reactions as illustrated in Schemes 1-8 to provide the instant compounds. Preparation of the instant compounds wherein X 1 is sulfur in its various oxidation states is shown in Scheme Intermediates LI-LIV may undergo the previously described reactions to provide the instant compounds.

Scheme 21 illustrated preparation of compounds of the formula A wherein Y is hydrogen. Thus, suitably substituted isonipecotic acid may be treated with N,O-dimethylhydroxylamine and the intermediate LV reacted with a suitably substituted phenyl Grignard reagent to provide intermediate LVI. That intermediate may undergo the reactions previously described in Schemes 1-8 and may be further modified by reduction of the phenyl ketone to provide the alcohol LVII.

Compounds of the instant invention wherein X1 is an amine moiety may be prepared as shown in Scheme 22. Thus the N-protected 4-piperidinone may be reacted with a suitably substituted aniline in the presence of trimethylsilylcyanide to provide the 4-cyano-4aminopiperidine LVIII. Intermediate LVIII may then be converted in sequence to the corresponding amide LIX, ester LX and alcohol LXI.

Intermediates LIX-LXI can be deprotected and can then undergo the reactions previously described in Schemes 1-8 to provide the compounds of the instant invention.

Preparations of compounds of formula B wherein X 2 is an amido or an amine moiety are illustrated in Schemes 23, 24 and 25. As is clear from the reaction illustrated, the intermediate LXIII can undergo any of the piperidine nitrogen reactions illustrated in Schemes 1-8 to provide the instant compounds.

Schemes 26-29 illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art.

WO 97/38665 WO 9738665PCTIUS97/06487 76 SCHEME 1 o N CO 2

CH

3 o R b

SL

o ,rj 0 2

CH

3 o iii R b 1. LIDA, -78 0

C

1) HO!, 0H 2 C1 2 2) LIAIH 4 sub HN' 1) (c0 2 0, E 3

N

2) NaH, CH 3 1 vRb IV sub v b V R b sub WO 97/38665 PCTIUS97/06487 77 SCHEME 2 Ra 1 o P' 0 2

CH

3 2.

sub

N

ACO

2

CH

3

NN

Rb IV I vsub

HCI

NaBH(OAC) 3 t 3 N CICH 2

CH

2

CI

(CH

2 )nCHO

N

C F 3

CO

2 H, 0H 2 01 2 (0 2

H

5 3 SiH C0 2 0H 3

N

Rb N b sub H

XVII

1) Ar CH 2 X, CH 3

CN

2) CF 3 00 2 H, CH 2 01 2 (0 2

H

5 3 SiH R b N XVIII sub WO 97/38665 WO 9738665PCTIUS97/06487 78 SCHEME 3 *0

H-N

Ilila

HCI

sub Boo NH ix Boc NH CHO NaBH(OAc)3 Et 3 N, CIOH 2

CH

2

CI

sub 2

CH

3 Boc NH BocHN i-C0 2

CH

3 0F 3 C0 2

H

CH

2 C1 2 sub CH3

NH

2

BOC

2 0

NH

2 sub Xl WO 97/38665 WO 9738665PCTIUS97/06487 79 SCHEME 3 (continued) Ra CHO i- C0 2 0CH 3 BocNH\ Nk- NaBH(OAc)3 b\ Et 3 N CICH 2

CH

2

CI

x NH 2 Rbb Rsu 00 2

CH

3

CF

3

CO

2 H, CH 2

CI

2 BocNH N NaHCO 3 NH Rb sub 0 2 0H 3

NC

NHL /N AgON NH Rb sub N N Nsub WO 97/38665 WO 9738665PCTIUS97/06487 80 SCHEME 4 N CH 2 00 2

H

N

H

CH

3 0H

HCI

.HOI

xIX (0 6

H

5 3 CBr

(C

2

H

5 3

N

DMF

1) ArCH 2 X OH 3

CN

ref lux 2) CH 3 OH, reflux xxi Ar- \N-CH 2

CO

2

CH

3

N

XXII

2.5N HOlaq 550C Ar- 0H 2 C0 2

H

N

N xl WO 97/38665 WO 9738665PCTJ(US97/06487 81 SCHEME 4 (continued) 0H 2 00 2 HC2H

HN

N

XXIII Illa R b sub EDC HOI HOBt

DMF

or 0

CO

2

CH

3 rN N b N- R b sub

XXIV

WO 97/38665 WO 9738665PCT/US97/06487 82 SCHEME 4 0 NaHMDS Br,_ Sub LiAIH 4 o0 COEt 0 Sub) O

OH

Sub HCI,

CH

2

CI

2

HOI*HN

R

8

N

EDO, HOAt -0C0 2

H

n IV Sub Sub WO 97/38665 PCTIUS97/06487 83 SCHEME 4b NC Ra

O

HC*HNC q IV Sub NaCNBH 3 NC

-\N

1 NaBO 3 Sub Sub WO 97/38665 WO 9738665PCT/US97/06487 -84- SCHEME 4c KH, (CH 3 2 S0 4 V Sub HCIHN\§0H HOI, EtOAc R 1 -N iPr 2 NEt Sub R a pJ

OCH

3

N-

N

N Sub WO 97/38665 WO 9738665PCT/US97/06487 85 SCHEME 4d O0r COR 0 c R =0H 3 ,0CH 3 0H 2 Sub HCI, EtOAc

POPR

(CF

3

SO

2 2 0 Sub WO 97/38665 WO 9738665PCTIUS97/06487 86 SCHEME 4e Cu(I)I N\ 0 2

CH

3

C'

1. H 2 Pt 2

O

2. (BoC) 2 0

-N

o0 N 0 2 0H 3 Br\ sub NaHMDS 1. HCI, EtOAc 2. iPr 2 NEt N

N

P0 2 0H 3 sub

CO

2

CH

3

N

sub WO 97/38665 WO 9738665PCT/IJS97/06487 87 SCHEME 4f Ra HNa CO 2

H

1. (BOC) 2 0 2. BnOH, EDO o o Ra 0 Sub 0 RaO NH Sub NaHMDS 1. H 2 Pd/C 2. NH 4 CI, EDO Sub WO 97/38665 WO 9738665PCT/US97/06487 88 SCHEME P- 0 2 0H 3

HN

Ci sub NaBH(OAc) 3 Et 3 N CICH 2

CH

2

CI_,.

BnOI BocNH

CHO

Vill xxv BocHN sub Xxv' F- C0J 2 0H 3

N

Rb sub xxvi" Pd(OH) 2

H

2

CH

3 0H 0H 3 C0 2

H

DMSO

CH

2

CI

2

(C

2

H

5 3

N

HO0 BocHN WO 97/38665 WO 9738665PCT/US97/06487 89 SCHEME 5 (continued)

H

BocHN Ra -l 2 0CH 3 Rb R'MgX (0 2

H

5 2 0 2. TEA,

CH

2 01 2 sub xxviII sub

XXIX

WO 97/38665 WO 9738665PCTfJS97/06487 90 SCHEME 6 NHBoc R b b sub

XXVII

CF

3

CO

2

H

CH

2

CI

2

ROHO

NaBH (OAc) 3

CICH

2

CH

2

CI

C0 2

CH

3 HO

N

NH

2

XXX

HO Np- C0 2 0CH 3 R'0H 2 sub

XXXI

WO 97/38665 WO 9738665PCTIUS97/06487 91 SCHEME 7 H H N, N 02 NaH, DMF 000 sub xxviI

R'SH

(0 2

H

5 3

N

CH

3 0H

N

Boc sub

XXXII

R'S C0 2 CH 3 BocHN Rb su R'S r- 00 2

CH

HOI

sub WO 97/38665 WO 9738665PCT/US97/06487 92 SCHEME 8

HO,

1) Boc 2 O, K 2 00 3 TH F-H 2 0 2) 0H 2

N

2 EtOAc

HO

BocNH C0 2

CH

3

XXXIV

xxxv

HO,

LiAIH 4

THE

0-200C

R'CH

2

X

CS

2

CO

3

DMF

BocNH' 'CH 2

OH

XXX

VI

BocNH CH 2 0H pyridine -SO 3

(C

2

H

5 3

N

200C

R'CH

2 0 ?o BocNH CHO

XXXVII

XXXVIII

WO 97/38665 WO 9738665PCTIUS97/06487 93 SCHEME 8 (continued)

R-CH

2 0 BocNH CHO xxxv"'l HN 0 2

H

Rb sub NaBH(OAc) 3 Vl

CICH

2

CH

2

CI

BocHN RD su XXXIX HOI ETOAc 1) 20% Pd(OH) 2

CH

3 OH, CH 3 00 2

H

2) HCI, EtOAc sub

HO'

NH-

2 sub WO 97/38665 PTU9/68 PCTfUS97/06487 94 SCHEME 9 00 0 sub MgBr

XLII

O-N OH HI 0 D sub

XLIII

HN OH K sub

XLIV

WO 97/38665 WO 9738665PCTIUS97/06487 95 SCHEME

OH

H-ND,

XLIV sub N- H 2 C0 2

H

N

xxiII EDC -HCI HOBt

DMF

A r 0 0

,OH

sub

XLV

WO 97/38665 WO 9738665PCTIUS97/06487 96 SCHEME 11 *0 1.POC1 3 pyridine 2. BH 3

H

2 0 2 NaOH sub

XLIII

OH

O sub *0 1.NaH, 0H 3 1 2. HOI

XLVI

)CH

3 ~sub

XLVII

WO 97/38665 WO 9738665PCT1US97/06487 97 SCHEME 12

OH

O sub 0

HOI

XLVI

__,sub NaBH(OAC) 3

EI

3 N CICH 2

CH

2

CI

(CH

2 )nCHO

N

Tr 7 sub II\o WO 97/38665 WO 9738665PCT/US97/06487 98 SCHEME 13 POCl 3 pyridine 2. H 2 Pd/C

XLIII

sub o sub -0

XLVIII

A

~sub

HOI

NNZ

XXIII

EDO HOI HOBt

DMF

0 -sub N:

N

WO 97138665 PCT/US97/06487 99 SCHEME 14

(BOC)

2 0 Aq NaOH Ra 0

OH

0T Y Rb Benzyl alcohol EDO, DMAP Ra 0 1.-Na HMVDS 2. benzyl bromide 0 Rb

H

2 Pd on C Ra sub WO 97/38665 WO 9738665PCT/US97/06487 100 SCHEME 14 (continued)

DPPA

NEt 3 oT0Y 0 sub 0.

sub 0 Rb

AC

2 0 Py 0

H

3 C" NH

R-

HN R b

HOI

(CH

2 )nCH0

N

Tr NaBH(OAc) 3 Et 3 N CICH 2

CH

2

CI

sub RaH 3

C-<

N

ITr sub WO 97/38665 WO 9738665PCTJUS97/06487 101 SCHEME ~J MsCI Py sub sub

HOI

HCI.

0

H

3 C..JIKPIl Ra N

HN\

sub WO 97/38665 WO 9738665PCTIUS97/06487 102 SCHEME 16

H

(BOC)

2 0 0 a- OH 0 ID

H

MsOI 2. KON 0 NaHMDS B r,, Sub O CN

-N

Sub HOI, EtOAc WO 97/38665 WO 9738665PCT1UJS97/06487 103 SCHEME 17

H

3 C_

QN

CH

3 m-OPBA 1. (CF 3 C0 2 2 2. Na 2 00 3

H

2 0

CH

3 HO N-

OH

HO\

N

OH

3 H0 2 C

C\

SOC'

2 S0012 c LiAlH~

N

CH

3 CI N-

OH

3

N

OH

3 HO

OH

3 S001 2

OH

3 WO 97/38665 PTU9/68 PCTIUS97/06487 104 SCHEME 17 (continued) N- LAIH 4

H

3 00 2 C cI HO N-

C'

SOC'

2 CI\ N-

CI

Na-\

H

3 C-

QN/

H 3 C 0o 0- S0012 m-CPBA HC 1. AC 2 0 2. NaOH 0- WO 97/38665 PTU9/68 PCT[US97/06487 105 SCHEME 18 0>~ +0 Sub NaHMDS LiAIH 4 0 pICOEt Sub O OH Siub HCI, CH 2

CI

2

HCI*HN

0OH Sub WO 97/38665 WO 9738665PCTIUS97/06487 106 SCHEME 19 0 I 0 0 2

R

0 R OH 3 0H 3 0H 2 0I 1 Sub NaHMDS C0 2

R

+0 L Sub Sub WO 97/38665 WO 9738665PCTIUS97/06487 107 SCHEME O -a 00 2

R

R OH 3

CH

3

CH

2 NaHMDS O-I V O 2

R

+0

S

Ra O r- OH

LI

sub 00H 3 sub Ra 0 0OH 3 O N S LiAIH 4 KH, CH 3

I

Na1O 4 Oxone sub o>I 00H 3 0Y LIV sub WO 97/38665 WO 9738665PCTIUS97/06487 108 SCHEME 21 Ra HNa CO 2

H

(BOC) 2 0 0

R

0 2. HNOH 3 (00H 3 N-0 EDO LV H 3 C OH 3 BrMg

R

Sub N~I +0 C0 Sub HOI, EtOAc 0 Sub iPr 2 NEt /I H N-

N

R N0 R1~~N 0 Sub

H

N

HO

LVII Sub NaBH 4 WO 97/38665 WO 9738665PCTIUS97/06487 109 SCHEME 22

H

2 N a C TMSCN,HOAc \H f LVIII sub

H

2 S0 4 RaCONH 2

ND

sub

LIX

1. NaOH 2. EtOH, H+ Ra

CO

2 Et N LiAIH 4

N

LX sub f-I OH N

X

N

H

sub

H

2 Pd/C Ra LXIIsu sub WO 97/38665 WO 9738665PCTf/US97/06487 110- SCHEME 23 0>

HNO

b romobenzene t-BuONa PdCI 2 (o-tol 3

P)

2 Naj 0

HOI

AcOH R p 0

RNH

2 NaBH(OAc) 3 0

-N

LiOI IN

NHR

EDC, HOBT

LXIII

Ra N N NN

RN

~R8 WO 97/38665 WO 9738665PCT/US97/06487 III SCHEME 24

N>

OHO

N

R N NHR 6 NaBH(OAC) 3 R6

N

N L\

N

benzaldehyde NaBH(OAC) 3 R 6

=H

R 8 R R8 WO 97/38665 WO 9738665PCTIUS97/06487 112 SCHEME

R

UNH

2 -a

R

UNH

bstituted benzaldehyde

.BH

3

CN

0

,N

LiOl

N

EDO, HOBT sub

R

N j0

NUN

sub WO 97/38665 WO 9738665PCT/US97/06487 113 SCHEME 26

H

2

N

13 1) HNO 2 ,Br 2 2) KMnO 4 3) MeOH,H+ MgCI R 8 00 2

CH

3 BrXNf ZnCI 2 ,NiCJ 2 (Ph 3

P)

2 NaBH 4 (excess)

R

8 S0 3 'Py, Et 3 N N1-

CHO

DMSO

WO 97/38665 WO 9738665PCTIUS97/06487 -114- SCHEME 27 1 EtO( O)CI Br C0 2 0H 3

N

R 8 MgCI N C0 2 0H 3 ieat

N

Zn, CuON 3. S, xylene, I NaBH 4 (excess) XR 8 SOTPy, Et 3

N

CHpOH DMSO

N

ZnCI 2 NiCI 2 (Ph 3

P)

2 NaBH 4 (excess) S0 3 -Py, Et 3

N

.CH

2

OH

DMSO

,CHO

WO 97/38665 WO 9738665PCTIUS97/06487 115 SCHEME 28 CH 3 B~r

N

1. LDA, C02 2. MeOH, H+ ZnCI 2 NiOI 2 (Ph 3

P)

2 NaBH 4 (excess)

R

8 qH 2 OH SO 3 'Py, Et 3

N

DMSO

CHO

WO 97/38665 PCT/US97/06487 116- SCHEME 29 N Br 1. LDA, C0 2 2. (CH 3 3 SiCHN 2

CO

2

CH

3 Br

R

8 Br Zn, NiCI 2 (Ph 3

P)

2 N 00 2

CH

3 excess NaBH 4 8 N

CH

2 0H

SO

3 -Py, Et 3

N

DMSO

R

8 N

CHO

WO 97/38665 PCT/US97/06487 117 The instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors.

Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity neurofibromin neu, scr, abl, Ick, fyn) or by other mechanisms.

The compounds of the instant invention inhibit farnesylprotein transferase and the farnesylation of the oncogene protein Ras.

The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors Rak et al. Cancer Research, 55:4575- 4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.

The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment. For example, a component of NF-1 is a benign proliferative disorder.

The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses Glenn et al. Science, 256:1331-1333 (1992).

The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation Indolfi et al. Nature medicine, 1:541-545(1995).

The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease Schaffner et al.

WO 97/38665 PCT/US97/06487 118- American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).

The instant compounds may also be useful for the treatment of fungal infections.

The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

For oral use of a chemotherapeutic compound according to this invention, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.

If desired, certain sweetening and/or flavoring agents may be added.

For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.

The compounds of the instant invention may also be coadministered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.

For example, the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents. Similarly, the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-1, restinosis, polycystic kidney WO 97/38665 PCT/US97/06487 -119disease, infections of hepatitis delta and related viruses and fungal infections.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.

The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, saline, at a pH level, 7.4. The solutions may be introduced into a patient's blood-stream by local bolus injection.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.

When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.

In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.

The compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and WO 97/38665 PCT/US97/06487 120quantity of farnesyl-protein transferase (FPTase) in a composition.

Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques.

Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.

It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain farnesyl-protein transferase and quantitating the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention. The concentration of a sufficiently potent inhibitor one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel) required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample.

WO 97/38665 PCT/US97/06487 121

EXAMPLES

Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof.

EXAMPLE 1 Preparation of N- [1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl methylphenyl)-4-hydroxy piperidine.

Step A: 1-Triphenvlmethyl-4-(hydroxvmethyl)-imidazole.

To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260 mmol) in dry DMF (250 ml) at room temperature was added triethylamine (90.6 ml, 650 mmol). A white solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) in of DMF (500 ml) was added dropwise. The reaction mixture was stirred for 20 hrs, poured over ice, filtered, and washed with ice water. The resulting product was slurried with cold dioxane, filtered, and dried in vacuo to provide the titled product as a white solid which was sufficiently pure for use in the next step.

Step B: 1-Triphenvlmethyl-4-(acetoxvmethyl)-imidazole.

The alcohol from Step A (260 mmol, prepared above) was suspended in pyridine (500 ml). Acetic anhydride (74 ml, 780 mmol) was added dropwise, and the reaction was stirred for 48 hrs during which it became homogeneous. The solution was poured into EtOAc, washed sequentially with water, 5% aqueous HCI solution, saturated aqueous NaHCO3, solution, and brine, the organic extracts were dried (Na2SO4), and concentrated in vacuo to provide the product as a white powder, which was sufficiently pure for use in the next reaction.

WO 97/38665 PCT/US97/06487 122- Step C: 1-(4-Cyanobenzyl)-5-(acetoxymethyl)-imidazole hydrobromide A solution of the product from Step B (85.8 g, 225 mmol) and 4-cyano benzyl bromide (50.1 g, 232 mmol) in EtOAc (500ml) was stirred at 60 °C for 20 hrs, during which a pale yellow precipitate formed. The reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt. The filtrate was concentrated in vacuo to a volume (200 ml), reheated at 60 °C for 2 hrs, cooled to room temperature, and filtered again. The filtrate was concentrated in vacuo to a volume (100 reheated at 60 oC for another 2hrs, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in methanol (500ml), and warmed to 60 After 2hrs, the solution was concentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a white solid which was used in the next step without further purification.

Step D: 1-( 4 To a solution of the acetate from Step C (50.4 g, 150 mmol) in 3:1 THF/water (1.5 1) at 0 OC was added lithium hydroxide monohydrate (18.9 g, 450 mmol). After lhr, the reaction was concentrated in vacuo, diluted with EtOAc (3 and washed with water, sat. aq. NaHCO3 and brine. The solution was then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification.

Step E: 1-(4-Cvanobenzvl)-5-imidazole carboxaldehyde.

To a solution of the alcohol from Step D (21.5 g, 101 mmol) in DMSO (500ml) at room temperature was added triethylamine (56 ml, 402 mmol), then SO3-pyridine complex (40.5 g, 254 mmol).

After 45 min, the reaction was poured into EtOAc, washed with water and brine, dried (Na2SO4), and concentrated in vacuo to provide the WO 97/38665 WO 9738665PCTIUS97/06487 123 aldehyde as a white powder which was sufficiently pure without further purification.

Step F: N-t-Butoxycarbonyl-4- 3 -methylphenyl)-4-hydroxy piperidine.

To a solution of 3-methyiphenyl magnesium bromide (58m1 of a IM solution in THF, 58.0 mmol) at 0 0 C was added a solution of N-t-butoxycarbonyl piperidin-4-one (10.0g, S3mmol) in THF (30m1) dropwise over 20mmn, and the reaction stirred under argon for a furthur 30mmn. The reaction was quenched by addition of sat NH4Cl solution (lO0ml), and diluted with EtOAc. The organic extracts were dried, (MgSO4) and the solvent evaporated in vacuo to afford the title compound of sufficient purity to be used in the next step.

IH NMR CD30D 8 7.31 (1H, 7.28-7.16(2H, in), 7.05(1H, brd, J=7.lHz), 3.97(2H, d, J=l3Hz), 3.40-3.10(2H, in), 2.35(3H, 1.94(2H, dt, J=4.4 and 12.7Hz), 1.70(2H, d, J=12.7Hz) and 1.49(9H, s)ppin.

Step G: 4 -(3-Methylphenvl)-4-hvdroxypiperidine hydrochloride.

To a solution of N-t-butoxycarbonyl-4-(3-methylphenyl){..

hydroxy piperidine (0.546mg, 1 .87mmol) in EtOAc (30m1) at 0 0 C was bubbled gasseous HCl until saturated. After 10 min the solvent was evaporated in vacuc to afford the title compound of sufficient purity to be used in the next step.

IH NMR CD30D 5 7.33 (1H, 7.32-7.16(2H, mn), 7.10(1H, brd, J=7.OHz), 3.44(2H, t, J=14Hz), 3.40-3.20(2H, mn), 2.36(3H, 2.24(2H, dt, J'=4.4 and 13.5Hz) and 1.92(2H, d, J=13.5Hz)ppm.

Step H: N-1{ [1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yllmethyl methylphenyl)-4 hydroxvy p2iperidine.

To a mixture of 4 3 -methylphenyl)-4-hydroxypiperidine hydrochloride (457mg, 2.O0mmol), the aldehyde from step E (508mg, 2.4lmmol), and 3A molecular sieves (2.0 g) in methanol (20 ml) was added sodium cyanoborohydride (2.20 ml of a IM solution in THF, 2.20 inmol). The pH was adjusted to 5 by addition of acetic acid and the WO 97/38665 PCT/US97/06487 124reaction stirred under argon for 48hrs at room temperature. The solids were removed by filtration and the filtrate partitioned between EtOAc and saturated NaHCO3 solution, the organic extracts were dried (MgSO4), and the solvent evaporated in vacuo. The residue was purified by chromatography (Si02, gradient elution, 5 to 7% MeOH in methylene chloride. The residue was converted to the corresponding hydrochloride salt by its treatment with a solution of two equivalents of HC1 in aqueous acetonitrile and subsequent evaporation of solvents in vacuo.

Anal. Calcd for C24H26N40-2.0HC1-0.95H 2 0: C, 60.49; H, 6.32; N, 11.76. Found: C, 60.32; H, 6.42; N, 11.95.

FAB HRMS exact mass calcd for C24H27N40: 387.218487 found 387.218317.

1 H NMR CD30D 5 9.00 (1H, 8.09 (1H, 7.84 (2H, d, J=8.4Hz), 7.56 (2H, d, J=8.4Hz), 7.35 (1H, 7.30 (1H, d, J=7.7Hz), 7.24 (1H, t, J=7.4Hz), 7.10 (1H,d, J=7.4Hz), 5.82 (2H, 4.56 (2H, 3.65-3.45 (4H, 2.52 (2H, 2.35 (3H, s) and 1.94 (2H, d, J=14.4Hz) ppm.

EXAMPLE 2 Preparation of [1-(4-Cyanobenzyl)-1H-imidazol-5-yl]methyl chlorophenvl)-4 hydroxy piperidine.

The title compound was prepared according to the procedure in Example 1, Steps F-H replacing 3-methylphenyl magnesium bromide with 3-chlorophenyl magnesium bromide.

Anal. Calcd for C23H23N40C1-2.0HC1-0.35H20*0.20CH 3 CN: C, 56.85; H, 5.36; N, 11.90. Found: C, 56.83; H, 5.38; N, 11.89.

FAB MS 407 1 H NMR 8 CD30D 9.02 (1H, 8.15 (1H, 7.84 (2H, d, 7.60 (2H, d, J=8.0Hz), 7.59 (1H, 7.45 (1H, d, J=7.7Hz), 7.36 (1H, t, 7.29 (1H, d, J=7.7Hz), 5.87 (2H, 4.58 (2H, 3.65-3.45 (4H, 2.59 (2H, m) and 1.94 (2H, d, J=14.3Hz) ppm.

WO 97/38665 PCT/US97/06487 125 EXAMPLE 3 Preparation of [1-(4-Cyanobenzyl)-1H-imidazol-5-yl]methyl methylbenzyl)isonipecotic acid methyl ester.

Step A: N-t-Butoxycarbonyl isonipecotic acid.

To a solution of isonipecotic acid (25.8 g, 200 mmol) in 1 M aqueous NaOH (223 ml, 223 mmol) was added a solution of di-t-butyl dicarbonate in THF (200 ml) over 1 hr. The resulting solution was stirred at room temperature for 16hrs. The reaction mixture was then concentrated in vacuo to remove the THF and the residual aqueous solution extracted with hexane The hexane extracts were combined and back extracted with saturated NaHCO3. All of the basic aqueous solutions were combined and cooled to 0°C and then acidified with a 15% aqueous KHSO4 solution to a pH of 1-2. The resulting thick slurry was extracted with EtOAc combined and washed with brine, dried (MgSO4) and concentrated in vacuo to afford the product as a white solid.

Step B: N-t-Butoxycarbonvl isonipecotic acid methyl ester To an ice cold solution of N-t-butoxycarbonyl isonipecotic acid (8.8 g, 34.9 mmol), in a 10% mixture of methanol in benzene (250 ml), was added a 2.0 M solution of trimethylsilyldiazomethane in hexanes, dropwise, until a consistent yellow color was obtained ml). After vigorous gas evolution had ceased, the reaction mixture was stirred for 1 hr at room temperature. The mixture was then treated dropwise with glacial acetic acid until the yellow color had dissipated.

The reaction was stirred 15 min. and concentrated in vacuo to a pale yellow oil. The residue was purified by chromatography (SiO2,eluting with 20% EtOAc in hexanes). Evaporation of the solvent in vacuo afforded the product as a colorless oil.

WO 97/38665 PCT/US97/06487 126- Step C: N-t-Butoxycarbonyl-4-(2-methylbenzyl)-isonipecotic acid methyl ester To a solution of N-t-butoxycarbonyl isonipecotic acid methyl ester (10.1g 41.8 mmol) in 140 ml of dry THF at -78 C was added LDA (59 ml of a 1.0 M solution in THF, 59 mmol) over min. The resulting orange solution was stirred at -78 0 C for 1 hr and then treated dropwise with 2-methylbenzyl bromide (6.80 ml, 50.7 mmol) and then allowed to warm slowly to room temperature over 16 hrs. The reaction was quenched with saturated aqueous NH4C1, diluted with H20, and extracted with EtOAc. The combined organic extracts were washed with brine and concentrated in vacuo to an orange gum.

Chromatography (SiO2, eluting with 20 to 30% EtOAc in hexanes) and evaporation of solvent in vacuo, afforded the product as a white solid.

Step D: 4-(2-Methylbenzyl)-isonipecotic acid methyl ester hydrochloride salt.

To a solution of N-t-butoxycarbonyl-4-(2-methylbenzyl)isonipecotic acid methyl ester (7.13g, 20.5mmol) in EtOAc (100 ml) at 0°C. was bubbled HCI gas until saturated. The reaction was stirred for 10min at 0°C and the solvent evaporated in vacuo to afford the product as a white solid.

1 H NMR CD30D, 6 7.25-7.00(4H, 3.70(3H, 3.30(2H, m), 2.98(2H, 2.85(2H, dt, J=2.5 and 13.5Hz), 2.36(2H, d, J=15.0Hz), 2.29(3H, s) and 1.76(2H, m)ppm.

Step E: [1-(4-Cyanobenzyl)- 1H-imidazol-5-yl]methyl methylbenzvl)isonipecotic acid methyl ester.

The title compound was prepared using the procedure from example 1 step H and the hydrochloride salt from Step

D.

FAB HRMS exact mass calcd for C27H31N402 443.244702(MH+); found 443.245590.

Anal. Calcd for C27H30N402*2.95TFA: 0.35H20: C, 50.32 H, 4.32; N, 7.14. Found: C, 50.30; H, 4.28; N, 7.10.

WO 97/38665 PCT/US97/06487 127- EXAMPLE 4 Preparation of [1-(4-Cyanobenzyl)-1H-imidazol-5-yl]methyl methylphenvl)-4 hydroxy piperidine.

Step A: IH-Imidazole-4- acetic acid methyl ester hydrochloride.

A solution of 1H-imidazole-4-acetic acid hydrochloride (4.00g, 24.6 mmol) in methanol (100 ml) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature for 18 hrs. The solvent was evaporated in vacuo to afford the title compound as a white solid.

1 H NMR CDC13, 8 8.85(1H, 7.45(1H, 3.89(2H, s) and 3.75(3H, s) ppm.

Step B: 1-(Triphenylmethyl)- 1H-imidazol-4-ylacetic acid methyl ester.

To a solution of the product from Step A 24 0.141mol) in DMF (115ml) was added triethylamine (57.2 ml, 0.412mol) and triphenylmethyl bromide (55.3g, 0.171mol) and the suspension was stirred for 24 hrs. After this time, the reaction mixture was diluted with EtOAc and water. The organic phase was washed with saturated aqueous NaHCO3, dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by chromatography (SiO2, gradient elution, 0-100% EtOAc in hexanes; to provide the title compound as a white solid.

1H NMR CDC13, 8 7.35(1H, 7.31(9H, 7.22(6H, 6.76(1H, 3.68(3H, s) and 3.60(2H, s) ppm.

Step C: [1-(4-Cyanobenzyl)- 1H-imidazol-5-yl]acetic acid methyl ester.

To a solution of the product from Step B (8.00g, 20.9mmol) in acetonitrile (70 ml) was added 4-cyanobenzyl bromide (4.10g, 20.92 mmol) and heated at 55 0 C for 3 hr. After this time, the WO 97/38665 PCT/US97/06487 128reaction was cooled to room temperature and the resulting imidazolium salt was collected by filtration. The filtrate was heated at 55°C for 18hrs. The reaction mixture was cooled to room temperature and evaporated in vacuo. To the residue was added EtOAc (70 ml) and the resulting precipitate collected by filtration. The precipitated imidazolium salts were combined, suspended in methanol (100 ml) and heated to reflux for 30 min. After this time, the solvent was removed in vacuo,. The resulting residue was suspended in EtOAc (75ml) and the solid isolated by filtration and washed with EtOAc. The solid was treated with saturated aqueous NaHCO3 solution (300ml) and CH2C12 (300ml) and stirred at room temperature for 2 hrs. The organic layer was separated, dried (MgSO4) and evaporated in vacuo to afford the title compound as a white solid 1 HNMR CDC13, 5 7.65(1H, d, J=8Hz), 7.53(1H, 7.15(1H, d, J=8Hz), 7.04(1H, 5.24(2H, 3.62(3H, s) and 3.45(2H, s) ppm.

Step D: [1-(4-Cvanobenzvl)- 1H-imidazol-5-vllacetic acid.

A solution of [1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid methyl ester 4 .44g, 17.4mmol in THF (100ml) and 1 M lithium hydroxide (17.4 ml, 17.4 mmol) was stirred at room temperature for 18 hrs. 1 M HC1 (17.4 ml) was added and the THF removed by evaporation in vacuo. The aqueous solution was lyophilised to afford the title compound containing lithium chloride as a white solid.

1H NMR CD30D, 8 8.22(1H, 7.74(1H, d, J=8.4Hz), 7.36(1H, d, J=8.4Hz), 7.15(1H, 5.43(2H, s) and 3.49(2H, s) ppm.

Step E: [1-(4-Cyanobenzyl)- H-imidazol-5-yl]acetyl}-4-(3methylphenyl)-4 hydroxy piperidine.

To a mixture of the piperidine hydrochloride from example 1 step G (102mg, 0.447mmol), 4 yl]acetic acid (from step D) (127mg, 0.447mmol), HOOBT 7 3mg, 0.447mmol) and triethylamine (0.187ml, 1.34mmol) in DMF (3ml)was added EDC (86mg, 0.447mmol) and the reaction stirred at room temperature for 18 hrs. The reaction was diluted with EtOAc and WO 97/38665 PCT/US97/06487 129 washed with saturated NaHCO3 solution. The organic extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by preparative HPLC (C-18, gradient elution, 95:5 to 5:95 water: acetonitrile containing 0.1% trifluoroacetic acid). Lyophilization afforded the title compound as a white powder.

Anal. Calcd for C25H26N402.1.60 TFA: 0.65H20: C, 55.65 H, 4.79; N, 9.21. Found: C, 55.68 H, 4.79; N, 8.98.

FAB HRMS exact mass calcd for C25H27N402: 415.213401 found 415.212530.

1 H NMR CD30D 8 8.95 (1H, d, 1.4Hz), 7.78 (2H, d, J=8.5Hz), 7.53 (1H, 7.49 (2H, d, J=8.5Hz), 7.27 (1H, 7.30-7.20 (2H, 7.07 (1H, d, J=7.0Hz), 5.53 (2H, 4.34 (1H, d, J=11.0Hz), 3.95 (2H, s), 3.76 (1H, d, J=11.0Hz),3.50 (1H, dt, J=2.3 and 12.5Hz), 3.13 (1H, dt, J=2.7 and 12.5Hz), 2.35 (3H, s) and 2.10-1.60 (4H, m) ppm.

EXAMPLE Preparation of [1-(4-Cyanobenzyl)-1H-imidazol-5-yl]acetyl methylbenzyl)isonipecotic acid methyl ester.

The title compound was prepared using the procedure from example 4 step E substituting 4 2 -methylbenzyl)-isonipecotic acid methyl ester for 4 -(3-methylphenyl)-4-hydroxypiperidine hydrochloride (from example 3 step E).

1 H NMR CD30D 8 8.94 (1H, d, 1.4Hz), 7.72 (2H, d, J=8.0Hz), 7.48 (1H, 7.43 (2H, d, J=8.0Hz), 7.20-6.97 (4H, 5.46 (2H, 4.28 (1H, d, J=l Hz), 3.85 (2H, 3.76 (1H, d, J=11.0Hz), 3.67 (3H, 3.02 (1H, 2.93 (2H, 2,57 (1H, dt, J=3.0 and 19.0Hz), 2.29 (3H, s), 2.20 (2H, d, J=20.0 Hz), and 1.60-1.38 (2H, m)ppm.

Anal. Calcd for C28H30N403*1.70TFA, 0.35H20: C, 56.23 H, 4.87; N, 8.35. Found: C, 56.21; H, 4.86; N, 8.75.

WO 97/38665 WO 9738665PCT/US97/06487 130 EXAMPLE 6 Preparation of N- -(4-Cyanobenzyl)- IH-imidazol-5-yl] acetyl methylbenzyl))isonipecotic acid methyl ester.

The title compound was prepared using the procedure above substituting 2-methylbenzyl bromide with 4-methylbenzyl bromide FAB MIS 47 1(MH+).

Anal. Calcd for C28H31IN403-1.95HC1: 0.05H20: C, 61.98 H, 5.95; N, 10.33. Found: C, 62.00; H, 5.89; N, 10.38.

EXAMPLE 7 Preparation of N- -(4-Cyanobenzyl)-l1H-imidazol-5 -yllacetyl methylbenzyl))isonipecotic acid methyl ester.

The title compound was prepared using the procedure above substituting 2-methylbenzyl bromide with 3 -methylbenzyl bromide FAB MS 47 1(MH+).

Anal. Calcd for C28H31IN403-1.8OHCl: 0.05H20: C, 62.62H, 5.99; N, 10.43. Found: C, 62.59; H, 5.96; N, 10.36.

EXAMPLE 8 Preparation of N- (4-Cyanobenzyl)- 1H-i midazol-5-yl] acetyl (2,4-dichlorobenzyl))isonipecotic acid methyl ester.

The title compound was prepared using the procedure above substituting 2-methylbenzyl bromide with 2,4-dichlorolbenzyl bromide FAB MS 525(MH+).

WO 97/38665 WO 9738665PCT/US97/06487 131 Anal. Calcd for C27H26N403C12*1.OHCl.1I.60H 2 0: C, 54.90H, 5.15; N, 9.48. Found: C, 54.85; H, 4.76; N, 9.47.

EXAMPLE 9 Preparation of N- -(4-Cyanobenzyl)- 1H-irnidazol-5-yllacetyl methoxvbenzylbisonipecotic acid methyl ester.

The title compound was prepared using the procedure above substituting 2-methylbenzyl bromide with 3-methoxybenzyl bromide FAB MS 487(MH+).

Anal. Calcd for C27H26N403C12.1.8OHCl: C, 60.90; H, 5.80; N, 10. Found: C, 60.90; H, 5.77; N, 10.13.

EXAMPLE Preparation of N- -(4-Cyanobenzyl)- 1H-imidazol-5-yl] acetyl 1nap~hthylmethyl)isonipecotic acid methyl ester.

The title compound was prepared using the procedure above substituting 2-methylbenzyl bromide with 1 -naphthyl methyl bromide.

FAB HRMS exact mass calcd for C27H28N403C1: 507.2396 16(MH+); found 507.239124.

Anal. Calcd for C31lH30N403-2.25TFA: 0.40H20: C, 55.35 H, 4.32; N, 7.27. Found: C, 55.36H, 4.30; N, 7.36.

EXAMPLE 11 Preparation of N- -(4-Cyanobenzyl)- 1H-imidazol-5-yl] acetyl (4chlorobenzyl)isonipecotic acid methyl ester.

WO 97/38665 PCT/US97/06487 132- The title compound was prepared using the procedure above substituting 2-methylbenzyl bromide with 4-chlorobenzyl bromide.

FAB HRMS exact mass calcd for C27H28N403C1: 4 91.184994(MH+); found 491.184736.

Anal. Calcd for C27H27N403C1l2.30 TFA: 0.15H20: C, 50.21 H, 3.95; N, 7.41. Found: C, 50.18 H, 3.95; N, 7.46.

EXAMPLE 12 Preparation of N- [1 -(4-Cyanobenzyl)-1 H-imidazol-5-yl]acetyl} -4- (2,3-dichlorobenzvl)isonipecotic acid methyl ester.

The title compound was prepared using the procedure above substituting 2 -methylbenzylbromide with 2,3- dichlorobenzyl bromide.

FAB HRMS exact mass calcd for C27H27N403C12: 525.146021 found 525.144945.

Anal. Calcd for C27H26N403C1 2 *1.85 TFA: 0.45H20: C, 49.53 H, 3.89; N, 7.53. Found: C, 49.51 H, 3.90; N, 7.73.

EXAMPLE 13 Preparation of N- 1-(4 aminocarbonvl 4 2 -methylbenzyl) isonipecotic acid methyl ester.

Step A: 1-(4 Cvanobenzvl)-5-nitro-1H-imidazole.

A solution of 4-nitroimidazole 2 ,25g, 19.9mmol) and 4cyanobenzyl bromide 3 .90g, 19.9mmol) in acetonitrile (10 ml) was stirred at 50C for 72 hrs. The reaction was allowed to cool to room temperature and diethyl ether (70ml) was added. The precipitate was removed by filtration and the filtrate partitioned between EtOAc and NaHCO3 solution. The organic extract was dried (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (SiO2, WO 97/38665 PCT/US97/06487 133 MeOH in CH2C12) to afford a solid that was triturated with hot ethanol, and washed with diethyl ether, to afford the product as an off white solid.

Step B: 1-(4 Cvanobenzvl)-5- amino-1H-imidazole hydrochloride.

A solution of 1-(4 cyanobenzyl)-5- nitro-1H-imidazole (100mg, 0.438mmol) and 10% palladium on carbon was hydrogenated in the presence of 1 equivalent of HC1 under Parr conditions for lhr.

Removal of the catalyst by filtration and evaporation of solvent in vacuo afforded the title compound.

1 HNMR CD30D, 8 8,47(1H, d, J=1.7Hz), 7.71(2H, d, J=8.4Hz), 7.50(2H, d, J=8.4Hz), 6,55(1H, d, J=1.7Hz) and 5.36(2H, s)ppm.

Step C: N- 1-(4 Cyanobenzyl)-1 H-imidazol-5-yl-aminocarbonyl 4-(2-methylbenzyl) isonipecotic acid methyl ester.

To a suspension of 4 2 -methylbenzyl)-isonipecotic acid methyl ester hydrochloride (50mg, 0.176mmol) in toluene (2 ml) was added phosgene (0.912ml of a 1.93M solution in toluene, 1.76mmol) and triethylamine (0.074ml, 0.528mmol) and the mixture stirred for 48 hrs at room temperature. The excess phosgene was removed by purging the solution with argon gas for 10min. The suspension was added to 1amino-1H-imidazole hydrochloride (100mg, 0.528mmol) in CH2C12 (10 ml) and the mixture stirrred at 50 0 C for 72 hrs. The solvent was evaporated in vacuo and the residue purified by preparative HPLC (C18, 95:5 to 5:95 water: acetonitrile containing 0.1% TFA). The residue after lyophilisation was partitioned between CH2C12 and saturated NaHCO3 solution. The organic extract was dried (MgSO4), and evaporated to dryness FAB MS 472 1 HNMR CDC13 5 7.60(2H, d, J=8.1Hz), 7.28-6.90(8H, 5.30(2H, 3.90(2H, d, J=13.1Hz), 3.65(3H, 2.86(2H, 2.80(2H,d, J=11.9Hz), 2.30-2.10( 5H, m) and 1.80-1.40(2H, m) ppm.

WO 97/38665 PCT/US97/06487 -134- EXAMPLE 14 2(R,S)-N [1-(4-Cyanobenzyl)- 1H-imidazol-5-yl]2-(4cvanobenzvl) I acetvl-4-(2-methylbenzvl)-isonipecotic acid methyl ester.

Step A: 1-(Triphenylmethyl)- I H-imidazol-4-yl cyanobenzyl)-acetic acid methyl ester.

A solution of 1-(triphenylmethyl)- 1H-imidazol-4-ylacetic acid methyl ester (977mg, 2.55mmol) in THF (25 ml) was cooled to -78 0 C. Lithium hexamethyldisilazide (2.68ml, 2.68mmol) was added dropwise and the reaction stirred 30min at -78 0 C. 4-Cyanobenzyl bromide (500.7mg, 2.68mmol) was added and the reaction stirred a furthur 4 hrs at -78C and then at -20 0 C for 12hr. The reaction was quenched with water (10ml) and saturated NaHCO3 solutuon (10ml) and extracted with EtOAc. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo.. Chromatography of the residue (SiO2, 3% MeOH in CH2Cl2) afforded the product.

1 HNMR CDCl3, 6 7.55-6.90(20H, 6.55(1H, 3.90(1H, t, J=7.7Hz), 3.66(3H, s) and 3.31(2H, m) ppm.

Step B: 2- 1-(Triphenylmethyl)- 1H-imidazol-4-yl cvanobenzvl)-acetic acid.

A solution of the 2-11 -(triphenylmethyl)- 1H-imidazol-4yl -2-(4-cyanobenzyl)-acetic acid methyl ester in THF was treated with 1 equivalent of IM lithium hydroxide solution. Upon consumption of starting material as determined by t.l.c, 1 equivalent of hydrochloric acid was added and the solution evaporated to dryness in vacuo. The material obtained in this manner could be used without furthur purification.

Step C: {1 -(Triphenylmethyl)- 1H-imnidazol-4-yl cyanobenzyl)-acetyl-4-(2-methylbenzyl) isonipecotic acid methyl ester.

WO 97/38665 PCT/US97/06487 135 To a mixture of 4 2 -methylbenzyl)-isonipecotic acid methyl ester hydrochloride (72mg, 0.25mmol), and 1- (triphenylmethyl)- 1 H-imidazol-4-yl 1-2-( 4 -cyanobenzyl)-acetic acid(123mg, 0.25mmol), HOOBT (42mg, 0.25mmol) and triethylamine (0.088ml, 0.636 mmol) in DMF (3ml), was added EDC (54mg, 0.25mmol) and the reaction stirred at room temperature for 18hrs. The reaction was diluted with EtOAc and washed with saturated NaHCO3 solution, the organic extracts were dried (Na2SO4), and the solvent evaporated in vacuo.. The residue was purified by chromatography(SiO2, gradient elution, 1-5%MeOH in CH2CI2) to afford the product.

Step D: 2(R,S)-N [1-(4-Cyanobenzyl)- 1 H-imidazol-5-yl]-2-(4cyanobenyl) acetyl-4-( 2 -methylbenzyl)-isonipecotic acid methyl ester.

To a solution of 1-(triphenylmethyl)-1Himidazol-4-yl -2-(4-cyanobenzyl) I -acetyl-4-(2-methylbenzyl)isonipecotic acid methyl ester (96mg, 0.338 mmol) in acetonitrile (2 ml), was added 4-cyanobenyl bromide (24.5mg, 0.338 mmol) and the mixture heated at 55oC for 5hrs. The solvent was evaporated and the residue purified by preparative HPLC (C18, gradient elution, 95:5 to 5:95 water:acetonitrile containing 0.1% TFA) to afford the title compound after lyophilisation.

FAB HRMS exact mass calcd for C36H36N503 586.281815(MH+); found 586.280827.

EXAMPLE Preparation of N- [1-(Naphth-2-ylmethyl)- IH-imidazol-5-yl] acetyl (2-methvlbenzvl)isonipecotic acid methyl ester.

Step A: 2- [1 -(Naphth-2-ylmethyl)- I1H-imidazol-5-yl)acetic acid methyl ester.

WO 97/38665 PCT/US97/06487 -136- To a solution of the product of example 4 step B (4.36g, 11.4 mmol) in acetonitrile (70 ml) was added 2-(bromomethyl)naphthalene and heated to 55°C for 4hr. The reaction was cooled to room temperature and the resulting white precipitate was collected by filtration. The filtrate was concentrated to 30 ml and heated at 55 0 C for 18 hr. After this time, the reaction was cooled to room temperature and the resulting white precipitate collected by filtration. The filtrate was concentrated to 10 ml volume and heated to 55°C for 1 hr. The reaction was cooled to room temperature and diluted with ethyl acetate (25 ml).

The resulting precipitate was collected by filtration and combined with the previous 2 precipitates in methanol (100 ml) and heated to reflux for min. After this time, the solvent was removed in vacuo and the resulting residue was partitioned between methylene chloride (200 ml) and saturated sodium bicarbonate solution (100 ml). The organic layer was evaporated to dryness in vacuo and the residue purified by chromatography (SiO2, gradient elution, 0-6% methanol in methylene chloride) to provide the title compound as an off white solid.

1 HNMR CDC13, 6 7.82(2H, 7.75(1H, 7.70(1H, 7.49(3H, 7.20(1H, d, J=8.4Hz), 7.06(1H, 5.32(2H, 3.57(3H, s) and 3.49(2H, s) ppm.

Step B: 1-(Naphth-2-ylmethyl)- 1H-imidazol-5-yl]acetic acid hydrochloride.

2- [1-(Naphth-2-ylmethyl)- 1H-imidazol-5-yl] acetic acid methyl ester (0.92g, 3.28mmol was dissolved in 2.5N hydrochloric acid 50ml and heated to 55 0 C for 3hr. After this time, the solution was concentrated to dryness in vacuo to give the title compound as a white solid.

1HNMR CD30D, 8 8.92(1H, 7.94(1H, d, J=8.6Hz), 7.88(2H, m), 7.83(1H, 7.54(3H, 7.43(1H, d, J=14.0Hz), 5.60(2H, s) and 3.82(2H, s) ppm.

Step C: N- [1 -(Naphth-2-ylmethyl)-1H-imidazol-5-yl]acetyl methylbenzvl)isonipecotic acid methyl ester.

WO 97/38665 PCT/US97/06487 -137- The title compound was prepared using the procedure from example 4 step E, substituting 4 -(2-methylbenzyl)-isonipecotic acid methyl ester hydrochloride for 4 -(3-methylphenyl)-4hydroxypiperidine hydrochloride and the acid from step B.

FAB HRMS exact mass calcd for C31H34N303 496.260017(MH+); found 496.260274.

Anal. Caled for C31H33N303*2.65HC1: C, 62.87 H, 6.07; N, 7.10.

Found: C, 62.85; H, 5.88; N, 7.14.

1 H NMR CD30D 8 8.96 (1H, 8.00-7.80(3H, min), 7.76(1H, s), 7.56(2H, min), 7.46(H, min), 7.35(1H, d, J=6.8Hz), 7.20-7.00(3H, min), 6.92(1H, d, J=7.0Hz), 5.56(2H, 4.18(1H, min), 3.80(2H, 3.62(3H, 3.62(1H, min), 3.0-2.70(3H, min), 2.35(1H, t, J=8.0Hz), 2.23(3H, s), 2.06(2H, d, J=13.3Hz) and 1.40-1.20(2H, m)ppm.

EXAMPLE 16 Preparation of N- [1-(4-Cyanobenzyl)- 1H-imidazol-5-yl]methyl methoxvmethvl-4-(2-methylbenzvl) piperidine.

Step A: N-t-butoxvcarbonvl isonipecotic acid benzvl ester.

To a solution of N-t-butoxycarbonyl isonipecotic acid (12.0 g, 52.3 mmol) from example 3 step A, in anhydrous CH2Cl2 (100ml), was added benzyl alcohol (6.0 ml, 58 mmol), followed by EDC (11.04 g, 57.6 mmol), and DMAP (642 mg, 5.25 mmol). The resulting mixture was stirred for 6 hrs, then diluted with CH2Cl2 (150 ml) and washed successively with water, 10% aqueous citric acid, saturated NaHCO3, and brine and dried (MgSO4). Concentration in vacuo afforded a colorless oil which was chromatographed (SiO2, 20% EtOAc in hexanes) to afford the product as a white solid.

Step B: N-t-Butoxycarbonyl-4-(2-methylbenzyl) isonipecotic acid benzvl ester.

To a solution of N-t-butoxycarbonyl isonipecotic acid benzyl ester (13.34 g, 41.8 mmol) in THF (100ml) at -78 0 C was added WO 97/38665 PCT/US97/06487 138sodium bis-trimethysilylamide (59 ml of a 1.0 M THF solution, 59 mmol) over 15 min. The resulting orange solution was stirred at -78 0

C

for 1 hr and then treated dropwise with 2-methyl benzyl bromide (6.80 ml, 50.7 mmol) and then allowed to warm slowly to room temperature over 16 hrs. The reaction was quenched with saturated aqueous NH4C1, diluted with H20, and extracted with EtOAc. The combined organic extracts were washed with brine, and concentrated in vacuo to an orange gum. Chromatography (SiO2, gradient elution, 20 to 30% EtOAc in hexanes) afforded the product as a white solid.

Step C: N-t-Butoxycarbonyl-4-hydroxymethyl-4-( 2 -methylbenzyl) piperidine.

To a suspension of lithium aluminum hydride (0.32 g, 8.4 mmol) in anhydrous ether (50 ml) was added a solution of 4-(2methylbenzyl)-N-t-butoxycarbonyl isonipecotic acid benzyl ester (3.0 g, 7.1 mmol) in anhydrous ether (25 ml) over 15 min. The resulting mixture was heated at gentle reflux for 1 hr. The reaction mixture was then quenched with the slow and successive addition of H20 (0.32 ml), aqueous NaOH (0.96 ml), and H20 (0.96 ml). After stirring for 30 min, the mixture was filtered through celite and the filtrate washed with brine, dried (MgSO4), and concentrated in vacuo to a colorless syrup. Purification by chromatography (SiO2, gradient elution, 25 to EtOAc in hexanes), afforded the product as a colorless gum. This material was recrystallized from EtOAc and hexane to afford a white solid. m.p. 104-106 0

C.

Step D: N-t-Butoxycarbonyl-4-methoxymethyl-4-(2methylbenzvl)piperidine To a suspension of sodium hydride (19 mg, 0.80 mmol) in 1.5 ml of THF, at 0°C was added a solution of N-t-butoxycarbonyl- 4-hydroxymethyl-4-(2-methylbenzyl)piperidine (200 mg, 0.63 mmol) in THF (1 ml The mixture was allowed to warm to room temperature.

To this suspension was added anhydrous DMSO (0.35 ml) and the mixture was heated to 60 0 C and stirred 5 hrs until the solution was WO 97/38665 PCT/US97/06487 139almost homogeneous. The reaction mixture was allowed to cool to room temperature and methyl iodide (0.070 ml, 1.12 mmol) was added.

The resulting heterogeneous mixture was stirred at room temperature for 16 hrs. The reaction mixture was treated with 10% aqueous citric acid and extracted with diethylether. The combined etheral extracts were washed successively with saturated aqueous NaHCO3 brine, dried (MgSO4), and concentrated in vacuo to a yellow gum. Chromatography (SiO2, 9% EtOAc in hexanes) afforded the product as a colorless gum.

Step E: 4-Methoxymethyl-4-( 2 -methylbenzyl)-piperidine hydrochloride salt.

N-t-Butoxycarbonyl-4-methoxymethyl-4-(2-methylbenzyl) piperidine was deprotected as in Example 1 Step G to afford the product as a white solid.

Step F: [1-(4-Cyanobenzyl)- 1H-imidazol-5-yl]methyl methoxvmethyl-4-(2-methylbenzyl) piperidine.

The title compound was prepared using the procedure from example 1 step H using 4 -methoxymethyl-4-(2-methylbenzyl) piperidine hydrochloride.

FAB HRMS exact mass calcd for C27H33N40 429.265437 found 429.265817.

1 H NMR CD30D 8 8.77 (1H, 7.79(2H, d, J=8.4Hz), 7.78(1H, s), 7.41(2H, d, J=8.4Hz), 7.20-7.05(4H, 5.61(2H, 4.36(2H, s), 3.36(3H, 3.35-3.10(6H, 2.78(2H, 2.31(3H, s) and 1.90- 1.60(4H, m)ppm.

EXAMPLE 17 Preparation of 4 -Cyanobenzyl)-lH-imidazol-5-yl]acetyl}--4methoxvmethyl-4-(2-methylbenzyl) piperidine.

WO 97/38665 WO 9738665PCTIUS97/06487 140 The title compound was prepared using the procedure from example 4 step E using 4 -methoxymethyl-4-(2-methylbenzyl) piperidine hydrochloride.

FAB HRMS exact mass calcd for C28H33N402 457.260352 found 457.260528.

1 H NMR CD30D 8 8.94 7.69(2H, d, J=8.4Hz), 7.47(1H, s), 7.41(2H, d, J=8.4Hz), 7.20-7.05(4H, in), 5.46(2H, 3.87(1H, in), 3.80(2H, in), 3.60(1H, mn), 3.36(3H, 3.26(2H, in), 3.15(11-, in), 2.77(2H, 2.33(3H, s) and 1.70-1.35(4H, m)ppin.

EXAMPLE 18 Preparation of N- (4-Cyanobenzyl)- 1H-iinidazol-5 -yllacetyl 1-4hydroxymethyl-4-(2-methylbenzvl) piperidine.

The title compound was prepared using the procedure from example 4 step E using 4-hydroxymethyl-4-(2-methylbenzyl) piperidine hydrochloride which was obtained from treatment of N.-tbutoxycarbonyl-4-hydroxyinethyl-4- (2-methylbenzyl) piperidine with gaseous HCl in EtOAc and evaporation of solvent.

Anal. Calcd for C27H30N402'1.75TFA.0.15H-20: C, 56.81; H, 5.01; N, 8.69. Found: C, 56.81; H, 5.02; N, 8.83.

EXAMPLE 19 Preparation of N- {f [1-(4-Cyanobenzyl)- 1 H-iinidazol-5-yl] ethyl I (2inethylbenzvhisonipecotic acid methyl ester.

Stejp A: 5- [1-(4-cvanobenzvl)- 1H-iinidazolvllethanol.

To a stirred solution of the ester from example 4 step C, (1 .50g, 5.88inmol), in methanol (20 ml) at 0 0 C, was added sodium borohydride (1.00g, 26.3inmol) portionwise over 5 min. The reaction was stirred at 0 0 C for 1 hr and then at room temperature for an additional 1 hr. The reaction was quenched by the addition of saturated WO 97/38665 PCT/US97/06487 141 NH4C1 solution and the methanol evaporated in vacuo.. The residue was partitioned between EtOAc and saturated NaHCO3 solution and the organic extracts dried, (MgSO4) and evaporated in vacuo. The residue was purified by chromatography (SiO2, gradient elution, 4 to methanol in methylene chloride) to afford the title compound as a white solid.

1 H NMR CDC13 8 7.64(2H, d, J=8.2Hz), 7.57(1H, 7.11(2H, d, J=8.2Hz), 6.97(1H, 5.23(2H, 3.79(2H, t, J=6.2Hz), 2.66(2H, t, J=6.2Hz) ppm.

Step B: 4 -Cvanobenzvl)-imidazolvl)ethvlmethanesulfonate.

A solution of 5-[1 -(4-cyanobenzyl)- 1H-imidazolyl]ethanol (0.500 g, 2.20 mmol) in methylene chloride (6 ml) at 0°C was treated with Hunig's base (0.460ml, 2.64mmol) and methanesulfonyl chloride (0.204ml, 2.64mmol). After 2 hrs, the reaction was quenched by addition of saturated NaHCO3 solution (50ml) and the mixture extracted with methylene chloride (50ml), dried (MgSO4) and the solvent evaporated in vacuo. The title compound was used without furthur purification.

1 H NMR CDC13 5 7.69 (1H, s) 7.66(2H, d, J=8.2Hz), 7.15 (2H, d, J=8.2Hz), 7.04(1H, 5.24(2H, 4.31(2H, t, J=6.7Hz), 2.96(3H, s), and 2.88(2H, t, J=6.6Hz)ppm.

Step C: [1-(4-Cyanobenzyl)-1H-imidazol-5-yl]ethyl methylbenzvl)isonipecotic acid methyl ester.

A solution of 5-(-1-(4-cyanobenzyl)-imidazolyl) ethyl methanesulfonate (223 mg, 0.73 mmol) in DMF (6.0 ml) was added to 4-(2-methylbenzyl isonipecotic acid methyl ester hydochloride (207.2mg, 0.73mmol), sodium iodide (438mg, 2.92 mmol) and K2C03 (252mg, 1.82mmol). The mixture was stirred at 55 0 C for 3 hrs and the solvent evaporated in vacuo. The residue was purified by preparative HPLC (C18, gradient elution, 95:5 to 5:95% water: acetonitrile, containing 0.1% TFA). Lyophilisation afforded the TFA salt which was converted to the HC1 salt, by partioning between CH2C12 and a saturated WO 97/38665 WO 9738665PCTIUS97/06487 142 NaHCO3 solution. The organic extract was dried (MgSO4 and treated with aqueous HCl in acetonitrile and lyophilised.

Anal. Caled for C28H32N402'2.55HC1.2.55H 2 0: C, 56.14; H, 6.74; N, 9.35. Found: C, 56.12; H, 6.74; N, 9.02.

FAB HRMS exact mass calcd for C28H33N402 457.260352 found 457.260675.

IH NMR CD30D 8 9.05 (1H, 7.80(2H, d, J=8.2Hz), 7.61(]H, s), 7.53(2H, d, J=8.2Hz), 7.20-7.00(4H, in), 5.66(2H, 3.71(3H, s), 3.58(2H, d, J=12.3), 3.38(2H, in), 3.18(2H, in), 2.90(2H, 2.90(2H, t, J=l3Hz), 2.40(2H, d, J=12.2Hz), 2.37(3H, s),and 2.10(2H, t, J=12.2Hz) ppm.

EXAMPLE Preparation of N- 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]methyl I -trans- 4- (3-methvlp~henvl )-3-hvdroxypiperidine.

StepA N-.t-B utoxycarbonyl-4- (3-methyiphenvl ).-iperid-3 -ene.

To a solution of N-t-butoxycarbonyl-4-(3-rnethylphenyl).4hydroxy piperidine (from example 1 step (1.57g, 5.4Ommol) in pyridine (25 ml) at 0 0 C was added phosphorous oxychloride (1.01 ml, 1 0.7inmol) and the reaction stirred 16 hrs at room temperature. The reaction was diluted with water and partitioned between EtOAc and aqueous citric acid solution. The organic extracts were washed with NaHCO3 and brine, dried (MgSO4), and the solvent evaporated in vacuo. Chromatography of the residue (SiO2, 10:90 EtOAc in hexanes) afforded the product as an oil.

1 H NMR CDC13 6 7.40-7.00(4H, in), 6.03(IH, 4.08(2H, s),3.64(2H,t, J=5.5Hz), 2.52(2H, 2.37(3H, s) and 1.51(9H, s)ppm.

Ste B:trans-N-t-B utoxycarbonyl-4- (3 -methylphenyl)- 3 hydroxy pi1peridine To a solution of N-t-butoxycarbonyl-4- (3-methyiphenyl)piperid-3-ene, (0.705g, 2.58minol) in THF (3 ml) at 0 0 C was added WO 97/38665 PCT/US97/06487 143 borane (3.09ml of a 1M solution in THF, 3.09 mmol) and the reaction stirred 4 hrs at room temperature. The reaction was cooled to 0°C and treated carefully with NaOH (3 ml of a 2.5M solution, and then hydrogen peroxide (10ml) and the reaction stirred for 2 hrs at room temperature. The reaction was diluted with water andextracted with EtOAc The organic extracts were washed with NaS203, brine, dried (MgSO4), and the solvent evaporated in vacuo.. Chromatography of the residue (SiO2, 25:75 EtOAc in hexanes) afforded the product as an oil.

1 H NMR CDC13 6 7.40-7.20(1H, 7.20-7.0(3H, 4.40(1H, brs), 4.18(1H, brs), 2.75(1H, 2.62(1H, 2.44(1H, 2.35(3H, s), 1.90-1.60(3H, 1.49(9H, s) ppm.

Step C: trans-4- (3-Methylphenyl)-3 hydroxypiperidine hydrochloride.

To a solution of trans -N-t-butoxycarbonyl-4- (3methylphenyl)-3 hydroxypiperidine, (0.20g, 0.12 mmol) in EtOAc ml) at 0°C was bubbled HC1 gas until saturated. The reaction was stirred at 0°C for 10 min and then the solvent evaporated in vacuo to afford the product as a white foam.

1 H NMR 8 CDC13 7.22(1H, t, J=7.3Hz), 7.20-7.0(3H, 3.95(1H, m), 3.54-3.36(2H, 3.07(1H, dt, J=3.3 and 14.6Hz), 2.84(1H, t, J=10.8Hz), 2.70(1H, 2.34(3H, 2.10-1.80(2H, m) ppm.

Step D: N- [1-(4-Cyanobenzyl)-1H-imidazol-5-yl]methyl} -trans-4- (3-methylphenvl)-3 hydroxv piperidine.

The title compound was prepared by the procedure in example 1 step H using trans- 4- (3-methylphenyl)-3 hydroxy piperidine hydrochloride.

Anal. Calcd for C24H26N402.55TFA*0.05H 2 0: C, 51.54; H, 4.26; N, 8.26. Found: C, 51.53; H, 4.24; N, 8.42.

FAB HRMS exact mass calcd for C24H27N40 387.218487 found 387.216845.

WO 97/38665 WO 9738665PCTfUS97/06487 144 EXAMPLE 21 Preparation of 4 -Cyanobenzyl)-1IH-imidazobsyllmethyl I -trans- 4- (3-methylphenyl)-3 methoxv-piperidine.

Step2 A: trans-N-t-Butoxycarbonyl-4- (3 -methylphenyl)-3 methioxy piperidine To a solution of trans-N-t-butoxycarbonyp4- (3methylphenyl)-3 hydroxy piperidine (I117mg, O.

4 O2mmol), in DMF (2 ml) at 0 0 C was added sodium hydride (24 mg of a 60% dispersion in mineral oil, 0.8O3mmol). After 10 min, methyl iodide (O.050m1, 0.8O3mmol) was added and the reaction allowed to warm to room temperature over 16 hrs. The reaction was quenched by the addition of saturated NH4Cl solution (5 ml) and extraction with EtOAc. The organic extracts were washed with brine and dried, (MgS 04) and the solvent evaporated in vacuo Chromatography of the residue (SiO2, EtOAc in hexanes) afforded the title compound as an oil.

1 H NMR CDC13 8 7.20(lH, t, J=7.5Hz), 7.20-7.0(3H, in), 4.50(1H, brs), 4.12(lH, brs), 3.28(1H, mn), 3.17(3H, 2.75(1H, t, J=12.3Hz), 2.60-2.45(2H, in), 2.34(3H, 1.85-1.60(2H, mn), 1.495(9H, s) ppm.

Step B: trans-4- (3-Methylphenyl)-3 inethoxy piperidine hydrochloride.

To a solution of trans-N-t-butoxycarbonylh4-. (3inethylphenyl)-3 methoxy piperidine, (0.20g, 0.65mmol) in EtOAc ml) at 0 0 C was bubbled HCl gas until saturated. The reaction was stirred at 0 0 C for 10 min and then the solvent evaporated in vacuo to afford the product as a white foam.

1 H NMR 8 CDC13 7.22(1H, t, J=7.3Hz), 7.20-7.0(3H, mn), 3.80-3.60(2H, in), 3.35(1H, mn), 3.15(3H, 3.07(IH, mn), 2.90-2.70(2H, in), 2.36(3H, s) and 2.10-1-95(2H, in) ppm.

Ste~p C: N-1{ [1 -(4-cyanobenzyl)-lIH-imidazol-5-yl] methyl -trans-4- (3 -methylphenyl)- 3-methoxy ieridine.

WO 97/38665 PCT/US97/06487 -145- The title compound was prepared by the procedure in example 1 step H using trans-4- (3-methylphenyl)-3 methoxy piperidine hydrochloride.

Anal. Calcd for C24H26N40*2.65TFA*0.45H20: C, 51.20; H, 4.47; N, 7.88. Found: C, 51.18; H, 4.45; N, 7.90.

FAB HRMS exact mass calcd for C25H29N40 401.234137 found 401.233036.

EXAMPLE 22 Preparation of N- [1-(4-cyanobenzyl)-1 H-imidazol-5-yl]methyl -trans- 4- (3-methlphenvl)-3 benzvloxy piperidine.

Steg A: trans-N-t-Butoxycarbonyl-4- (3-methylphenyl)-3 benzvloxy piperidine.

To a solution of trans-N-t-butoxycarbonyl-4- (3methylphenyl)-3 hydroxy piperidine (131mg, 0.449mmol), in DMF (2 ml) at OoC was added sodium hydride (27mg of a 60% dispersion in mineral oil, 0.890mmol). After 10 min, benzyl bromide (0.107ml, 0.890 mmol) was added and the reaction allowed to warm to room temperature over 16 hrs. The reaction was quenched by the addition of saturated NH4Cl solution (5 ml) and extraction with EtOAc. The organic extracts were washed with brine and dried (MgSO4) and the solvent evaporated in vacuo. Chromatography of the residue (SiO2, gradient elution, 10-15% EtOAc in hexanes) afforded the title compound as an oil.

1 H NMR CDC13 6 7.30-6.90(9H, 4.40(2H, brs), 4.25-4.05(2H, brs), 3.40(1H, 2.80-2.55(3H, 2.32(3H, 1.85-1.60(2H, m), 1.48(9H, s) ppm.

Step B: trans-4- (3-Methylphenyl)-3-benzloxypiperidine hydrochloride.

To a solution oftrans-N-t butoxycarbonyl-4-(3methylphenyl)-3-benzyloxy piperidine, (0.137g, 3.60mmol) in EtOAc WO 97/38665 WO 9738665PCTJUS97/06487 146 ml) at 0 0 C was bubbled HCl gas until saturated. The reaction was strirred at 0 0 C for 10 minl and then the solvent evaporated in vacuc to afford the product as a white foam.

111 NMR CD30D 8 7.30-6.90(9H, in), 4.37(1H, d, J=1 1.5Hz), 4.17(111, d, J= 11. 5Hz), 3.87(11H, dt, J=4.5 and 10.4Hz), 3.66(11H, dd, J=4.4 and 13.3Hz), 3.42(1H, d, J=12.3Hz), 3.07(1H, dt, 4.0 and 12.3 Hz), 2.93- 2.76(2H, in), 2.3 1(3H, s) and 2.20-1.93(2H, m) ppm.

Step C: N- -(4-Cyanobenzyl)- 1H-imidazol-5-yI] methyl -trans-4- (3-methvlphenyl)- 3-benzyloxy piperidine.

The title compound was prepared by the procedure in example 1 step H using trans-4-(3-methylphenyl)-3benzyloxypiperidine hydrochloride.

FAB HRMS exact mass calcd for C31H33N40 477.265437 found 477.265776.

EXAMPLE 23 Preparation of 1- [2(R,S)-Amino-3 -(2-tetradecyloxyphenyl)propyl] (2methylbenzyl)isonipecotic acid methyl ester dihydrochloride salt Step A: 3-(2-hydroxyphenyl)-2-(N-t-butoxycarbonylamino)p2ropanol To a solution of D,L-N-t-Butoxycarbonyl-ortho-tyrosine methyl ester (1.34 g, 4.54 inmol) in THF (20 mL) at 0 0 C was added lithium aluminum hydride (400 mg, 10.5 inmol) portionwise. After 4 hrs at room temperature, H20 (0.4 ml) was added dropwise followed by IN NaOH (0.4 ml) and then H20 (1.2 ml) The slurry was stirred for 1 hour, filtered through celite, rinsed with THF and the solvent was evaporated in vacuo.. Chromatography of the residue (SiO2, EtOAc in hexanes) gave the title compound as a solid.

Step B: 3- (2-Tetradecyloxyphenyl)-2(R, (N-t-butoxycarbonylamino )propanol.

WO 97/38665 PCT/US97/06487 147 A mixture of the alcohol from Step A (218 mg, 0.82 mmol), tetradecyl bromide (170 gL, 0.9 mmol) and CsCO3 (532 mg, 1.63 mmol) in DMF (8 mL) was stirred for 16 hs at room temperature under argon. The mixture was poured into water and extracted with EtOAc. The organic extracts were combined, washed with water and brine, dried (MgSO4), and concentrated in vacuo to give an oil.

Purification by chromatography (SiO2, 20% EtOAc in hexanes) gave the title compound as a solid.

Step C: 3-(2-Tetradecyloxyphenyl)-2(R,S)-(N-t butoxycarbonylamino)propanal To a solution of the alcohol from Step B (135 mg, 0.29 mmol) in CH2C12, (1.0 ml), DMSO, (1.0 ml) and Et3N (0.2ml) at room temperature under argon was added pyridine-S03 complex (185 mg, 1.17 mmol). The mixture was stirred for 3 hrs and then poured into brine, and extracted with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound as an oil.

1 H NMR CDC13 6 9.59 1H), 7.25-7.10 2H), 6.95-6.80 2H), 5.42 1H), 4.35 1H), 3.96 (brt, 2H), 3.13 2H), 1.82 2H), 1.50-1.20 31H), 0.89 (brt, 3H).

Step D: 1-[2(R,S)-N-t-Butoxycarbonylamino-3-(2tetradecyloxyphenyl)propyl]--4-(2-methylbenzyl) isonipecotic acid methyl ester.

The aldehyde (138 mg, 0.30 mmol) obtained in Step C was dissolved in dichloroethane (2.5 ml) and treated with the piperidine hydrochloride from example 3 step D (75 mg, 0.27 mmol) and Et3N (37.8 ml, 0.27 mmol). The solution was slurried with 4 A molecular sieves and stirred for 30 min at room temperature before adding sodium triacetoxyborohydride (172 mg, 0.81 mmol). After stirring for 18 hrs, the solution was filtered through celite. The filtrate was poured into EtOAc, washed with saturated NaHC03 solution, brine, dried (MgSO4), and concentrated in vacuo to give an oil. Purification by WO 97/38665 PCT/US97/06487 148chromatography (SiO 2 30% EtOAc in hexanes) gave the title compound.

1 H NMR CDC13, 8 7.06 6H), 6.83 2H), 5.01 (brs, 1H), 3.92 4H), 3.59 3H), 2.82 4H), 2.07 8H), 1.41 37H), 0.88 (brt, 3H).

Step E: 1-[2(R,S)-Amino-3-( 2 -tetradecyloxyphenyl)propyl]-4-( 2 methylbenzyl)isonipecotic acid methyl ester dihydrochloride salt A solution of the N-t-butoxycarbonylamine from Step D (186 mg) in EtOAc (20 mL) was treated with HC1 gas until saturated.

After 15 min, the solvent was removed in vacuo to give the crude product as a solid which was triturated with Et20/hexane. The solvent was decanted and the residue dried in vacuo to give the title compound.

Anal. Calcd. for C38H60N20 3 2.4 HCI: C, 67.07; H,9.24; N, 4.12.

Found: C, 67.10; H, 9.33; N, 4.29.

FAB MS 593 EXAMPLE 24 Preparation of N-2-(S)-aminolauroyl-4-(1-napthylmethyl) isonipecotic acid methyl ester.

Step A: (S)-3-(1-Oxolaurovl)-4-(phenvlmethyl-2-oxazolidinone.

To a solution of (S)-4-Benzyloxazolidinone (8.85 g, mmol) in 150 mL of anhydrous THF at -78 °C was added a 2.5 M solution of n-Butyllithium (25 mL, 52.5 mmol) over 10 min. After the addition, neat lauroyl chloride (12.7 mL, 55 mmol) was added and the resulting solution stirred at -78 °C for 0.5 hr. and then allowed to warm to room temperature over 0.5 hr. The mixture was quenched with saturated aqueous ammonium chloride and the solvent removed in vacuo. The residue was diluted with water and extracted with methylene chloride. The extracts were combined and washed with 1M WO 97/38665 PCT/US97/06487 149aqueous sodium hydroxide, brine, dried over sodium sufate and concentrated in vacuo to afford the product as a viscous yellow oil.

1 H NMR CDC13 8 7.20-7.40 5 4.70 m, 1 4.20 2 H), 3.3 dd, J= 13.3, 3.3 Hz, 1 2.90 2 2.80 dd, J= 13.3, 9.7 Hz, 1 H) 1.70 m, 2 1.3 0(m, 18 0.90 J= 6.7 Hz, 3 H) Step B: Preparation of (S)-3-(1-Oxo-(S)-2-azidolauroyl)-4- (phenylmethvl-2-oxazolidinone.

To a solution of 3 -(l-Oxolauroyl)-4-(phenylmethyl-2oxazolidinone.(3.6 g, 10 mmol) in anhydrous THF (60 ml), at -78 °C was added 21 ml of a 0.5 M solution of potassium hexamethyldisilazide in toluene, 10.5 mmol). The resulting solution was stirred at -78 °C for min. and then treated with a precooled solution of 2,4,6triisopropylbenzenesulfonyl azide in anhydrous THF (25 ml). Two minutes after the addition, glacial acetic acid (2.3 ml, 40 mmol) was added and the reaction mixture was warmed to 25 0 C in a water bath and stirred for 1.5 hrs. The reaction mixture was diluted with chloroform (300 ml) and washed successively with brine and dilute sodium bicarbonate solution. After drying over sodium sulfate the crude chloroform solution was concentrated in vacuo to a yellow oil which was chromatographed on (SiO2, 5% EtOAc in hexanes). Evaporation in vacuo to afforded the product as a pale yellow viscous oil.

1 H NMR CDC13 8 7.2-7.4 5 4.9 (dd, J=8.6, 5.0 Hz, 1 4.7 m, 1 4.2 2 3.4 dd, J= 13.4, 3.2 Hz, 1 2.8 (dd, J= 13.4, 9.5 Hz, 1 H) 1.8 m, 2 1.6- 1.2 18 0.9 J= 6.7 Hz, 3 H).

Step C. 2 -N-t-butoxycarbonylaminolauroyl)-4- (phenvlmethyl-2-oxazolidinone.

To an argon degassed solution of the above azide (2.88 g, 7.2 mmol) in ethyl acetate (150 mL) was added t-butoxycarbonyl anhydride (2.5 g, 11.5 mmol) and 10 palladium on charcoal catayst This mixture was vigorously stirred under a balloon of hydrogen for 2 hrs. The catalyst was removed by filtration through celitChromatography (SiO2, 15% EtOAc in hexanes) and evaporation WO 97/38665 PCT/US97/06487 150 of solventin vacuo, afforded the product as a white solid. m.p. 93.5- 94.5 0

C.

1 H NMR CDC13 8 7.2-7.4 5 5.4 1 5.2 br d, J= 9 Hz, 1 4.6 1 4.2 2 3.3 m, 1 2.8 m, 1 H) 1.8 1H), 1.6-1.2 m, 26 0.9 J= 6.7 Hz, 3 H).

Step D: Preparation of 2 -N-t-Butoxvcarbonvlaminolauric acid To an argon degassed solution of the above oxazolidinone in a 3:1 THF: water mixture, under argon at 0°C was added LiOH monohydrate (0.45g, 10.7 mmol). After stirring at 0 °C for 1.5 hrs, the mixture was diluted with 0.5 M aqueous sodium bicarbonate and extracted with methylene chloride. The aqueous portion was acidified with 3 M aqueous HCI and extracted with ethyl acetate. The combined extracts were dried (MgS04) and concentrated in vacuo to afford the product as a viscous oil.

1 H NMR (CDC13) d 5.0 (br d, J= 8 Hz, 1 4.3 1 1.8 1 1.7 m, 1 1.4 s, 9 H) 1.4-1.2 m, 16 0.9 J= 7 Hz, 3 H).

Step E: N-2-(S)-t-Butoxycarbonylaminolauroyl-4-(1napthylmethyl) isonipecotic acid methyl ester.

The title compound was prepared according to the procedure in example 10 using the acid prepared in step D.

Step F: N-2-(S)-Aminolauroyl-4-(1 -napthylmethyl)-isonipecotic acid methyl ester A solution of the product from Step E (100 mg) in EtOAc ml) was treated with HC1 gas until saturated. After 15 mins, the solvent was removed in vacuo to give the crude product which was purified by preparative HPLC (C18, gradient elution, 95:5 to 5:95 water:acetonitrile containing 0.1% TFA) to afford the title compound as a white solid after lyophilisation.

Anal. Calcd for C30H44N203*1.20TFA: C, 63.02 H, 7.38; N, 4.54.

Found: C, 63.05; H, 7.42; N, 4.43.

WO 97/38665 PCT/US97/06487 151 EXAMPLE 4-(Benzoxazolidin-2-one-1 1-[1 imidazolvlacetyllpiperidine hydrochloride Step A: Preparation of 1H-Imidazole-4- acetic acid methyl ester hydrochloride.

A solution of 1H-imidazole-4-acetic acid hydrochloride (4.00g, 24.6 mmol) in methanol (100 ml) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature (RT) for 18hr. The solvent was evaporated in vacuo to afford the title compound as a white solid.

Step B: Preparation of 1-(Triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester To a solution of the product from Step A 2 4.85g, 0.141mol) in dimethyl formamide (DMF) (115ml) was added triethylamine (57.2 ml, 0.412mol) and triphenylmethyl bromide(55.3g, 0.171mol) and the suspension was stirred for 24hr. After this time, the reaction mixture was diluted with ethyl acetate (EtOAc) (1 1) and water (350 ml). The organic phase was washed with sat. aq. NaHCO3 (350 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (SiO2, 0-100% ethyl acetate in hexanes; gradient elution) to provide the title compound as a white solid.

1H NMR (CDC13, 400 MHz) d 7.35(1H, 7.31(9H, 7.22(6H, m), 6.76(1H, 3.68(3H, s) and 3.60(2H, s) ppm.

Step C: Preparation of [1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid methyl ester.

To a solution of the product from Step B (8.00g, 20.9mmol) in acetonitrile (70 ml) was added bromo-p-toluonitrile (4.10g, 20.92 mmol) and heated at 55°C for 3 hr. After this time, the reaction was cooled to room temperature and the resulting imidazolium salt (white precipitate) was collected by filtration. The filtrate was WO 97/38665 PCT/US97106487 152heated at 55°C for 18hr. The reaction mixture was cooled to room temperature and evaporated in vacuo. To the residue was added EtOAc ml) and the resulting white precipitate collected by filtration. The precipitated imidazolium salts were combined, suspended in methanol (100 ml) and heated to reflux for 30min. After this time, the solvent was removed in vacuo, the resulting residue was suspended in EtOAc and the solid isolated by filtration and washed (EtOAc). The solid was treated with sat aq NaHCO3 (300ml) and CH2C12 (300ml) and stirred at room temperature for 2 hr. The organic layer was separated, dried (MgSO4) and evaporated in vacuo to afford the title compound as a white solid Step D: Preparation of [1-(4-cyanobenzyl)-lH-imidazol-5-yl]acetic acid.

A solution of [l-(4-cyanobenzyl)- acid methyl ester 4 .44g, 17.4mmol in THF (100ml) and 1 M lithium hydoxide (17.4 ml, 17.4 mmol) was stirred at RT for 18 hr. 1 M HC1 (17.4 ml) was added and the THF was removed by evaporation in vacuo. The aqueous solution was lyophilised to afford the titled compound containing lithium chloride as a white solid.

Step E: Preparation of 1-(tert-butoxycarbonyl)-4-[(2hvdroxyphenyl)aminolpiperidine A 500 mL round bottom flask under inert atmosphere is charged with a magnetic stirring bar, 6.6 g (60 mmol) 2 -aminophenol and 12 g (60 mmol) N-t-butyloxycarbonyl-4-piperidone. The solids are suspended in 50 mL each 1,2-dichloroethane and glacial HOAc, treated with 1 g powdered 4A molecular sieves, and stirred at room temperature 30 min. 12.8 g (60 mmol) NaBH(OAc)3 is added and the thick slurry stirred at room temperature 30 h. The reaction mixture is diluted with 200 mL CH2C12 and quenched slowly with saturated NaHCO3 solution, approx 100 mL. The layers are separated, the organic layer washed with 1 x 150 mL saturated NaHCO3 solution, dried over MgSO4, filtered and concentrated to provide a brown oil.

WO 97/38665 PCT/US97/06487 153 Flash chromatography on silica (1 to 3% MeOH in CH2C12 containing conc. NH40H) provided 16.8 g (57 mmol, 95%) of the desired aminoalcohol as a foam.

Step F: Preparation of 1-(tert-butoxycarbonyl)-4-(benzoxaxolidin- 2-one- -vl)piperidine A 1-L round bottom flask under inert atmosphere is charged with a magnetic stirring bar, 16.8 g (57 mmol) of the aminoalcohol from Step E and 500 mL freshly distilled THF, and the flask immersed in an ice-water bath. Stirring is initiated and when the solution becomes homogeneous, 12 mL (69 mmol) N,Ndiisopropylethylamine is added followed by 5.7 g (19.2 mmol) triphosgene in one portion. The reaction is stirred at 0°C 30 min and then the ice-water bath removed and the reaction allowed to stir 15 h, wherein a precipitate is formed. The reaction mixture is filtered, concentrated to an oil and partitioned between 400 mL EtOAc and 200 mL saturated Na2CO3 solution. The layers are separated, the organic layer washed with 200 mL saturated Na2CO3 solution, dried over MgS04, filtered and concentrated to an oil. Flash chromatography on silica (15 to 30 to 40% EtOAc in hexanes) provided 14.6 g (46 mmol, of the benzoxazolone as an amorphous solid.

Step G: Preparation of 4-(benzoxaxolidin-2-one-1-yl)piperidine hydrochloride A 1-L round bottom flask is charged with a magnetic stirring bar, 14.6 g (46 mmol) benzoxazolone from Step F and 120 mL isopropanol. 60 mL 8 N HCI is added, the reaction becomes homogeneous and it is stirred 15 h wherein a precipitate forms. The reaction is concentrated by rotary evaporation and the solid dried azeotropically with 2 x 150 mL toluene and the resulting off white solid dried under vacuum to provide 11.5 g (45 mmol, 99%) of the amine hydrochloride salt.

WO 97/38665 PCT/US97/06487 154 Step H: Preparation of 4 -(benzoxaxolidin-2-one-1-yl)-1-[1-(4cyanobenzyl)-5-imidazolylacetvl1piperidine hydrochloride To a solution of the acid from Step D (639 mg, 1.77 mmol), the amine hydrochloride salt from Step G (303 mg, 1.18 mmol), and HOOBT (295 mg, 1.81 mmol) in DMF (5 mL) was added EDC (347 mg, 1.81 mmol), followed by triethylamine (0.99 ml, 7.11 mmol).

The reaction was stirred at room temperature for 15 hrs, diluted with EtOAc, and the organic layer was washed with sat. aq NaHCO3, brine, and dried (Na2SO4). and evaporated in vacuo. The resulting product was purified by silica gel chromatography (59% acetone/CH 2 C12 with 1% MeOH) to provide the desired amide which was taken up in CH 2 C12 and treated with excess 1 M HCl/ether solution, and concentrated in vacuo. The titled product hydrochloride (391 mg) was isolated as a white solid.

FAB mass spectrum m/e 442 Analysis calculated for C 25

H

23

N

5 03 1.0 HC1 0.55 H 2 0: C, 61.55; H, 5.19; N, 14.36; Found: C, 61.51; H, 5.23; N, 15.56.

EXAMPLE 26 1,2-Dihydro-4(H)-3,1 -benzoxazin-2-one-1 -(4-cyanobenzyl)hydrochloride Step A: Preparation of 1-tert-butoxycarbonyl-4-[(2hydroxvmethyl)phenl aminolpiperidine N-t-butoxycarbonyl-4-piperidinone (20 g, 100 mmol), 2aminobenzyl alcohol (13 g, 110 mmol), and acetic acid (14 mL, 220 mmol) were dissolved in dry toluene (500 mL). The solution was refluxed under inert atmosphere with azeotropic removal of water for 16 h. The solution was cooled to ambient temperature and to it was added NaBH3CN (14 g, 220 mmol) and dry THF (200 mL). The reaction was stirred at ambient temperature for 24 h. The reaction was WO 97/38665 PCT/US97/06487 155concentrated under reduced pressure and the residue was dissolved in EtOAc (750 mL). The EtOAc layer was washed with saturated aqueous NaHCO3 (4 x 500 mL) and brine (250 mL). The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography, using a gradient elution of 15-30% EtOAc-hexanes.

The titled compound was obtained as a gum.

Step B: Preparation of 1-[(1-t-butyloxycarbonyl)piperidin-4-yl]- 1.2-dihvdro-4(H)-3.1 -benzoxazin-2-one The product form Step A (24 g, 78 mmol) was dissolved in dry THF (250 mL) and cooled to 0°C. To the solution was added diisopropylethylamine (41 mL, 240 mmol) and triphosgene (8.54 g, 28.8 mmol). The reaction was stirred at 0°C for lh, and then at ambient temperature for 72 h. Ether (250 mL) was added, the mixture was cooled to 0OC for 3 h and then filtered to remove the hydrochloride salt of DIEA. The filtrate solvents were removed under reduced pressure and the residue was dissolved in EtOAc (750 mL). The EtOAc solution was washed with aqueous citric acid (2 x 500 mL), water (250 mL), and saturated aqueous NaHCO3 (2 x 500 mL). The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was boiled in ether (ca. 200 mL) until the solid had dissolved. Cooling overnight gave the titled product as off-white crystals.

Step C: Preparation of 1-(4-piperidinyl)-1,2-dihydro-4(H)-3,1benzoxazin-2-one hydrochloride A stirred solution of the product from Step B (19 g, 57 mmol) in EtOAc (500 mL) was cooled to 0 HCI gas was bubbled through the solution for 30 min. Stirring was continued at 0 °C for 1 h, during which time a precipitate had formed, and then at ambient temperature for 1 h. The stirred suspension was cooled to 0°C and cold ether (250 mL) was added.

After 1 h at 0°C, the solid was collected by filtration. The solid was dried under reduced pressure for 18 h, giving the titled compound as an off-white solid.

WO 97/38665 PCT/US97/06487 156- Step D: Preparation of 4-(1,2-dihydro-4(H)-3,1-benzoxazin-2-one- 4 hydrochloride To a solution of the acid from Step D of Example 25 (435 mg, 1.21 mmol), the amine hydrochloride salt from Step C (215 mg, 0.796 mmol), and HOBT (168 mg, 1.24 mmol) in DMF (6 mL) was added EDC (233 mg, 1.22 mmol), followed by triethylamine (0.66 ml, 4.8 mmol) The reaction was stirred at room temperature for 15 hrs, diluted with EtOAc, and the organic layer was washed with sat. aq NaHCO3, brine, and dried (Na2SO4). and evaporated in vacuo. The resulting product was taken up in CH2C12 and treated with excess 1 M HCl/ether solution, and concentrated in vacuo. The titled product hydrochloride (335 mg) was isolated as a white solid.

FAB mass spectrum m/e 456 Analysis calculated for C 26

H

25

N

5 03 1.60 HCI 0.85 H 2 0: C, 59.05; H, 5.39; N, 13.24; Found: C, 59.10; H, 5.40; N, 12.76.

EXAMPLE 27 4-(1,2-Dihydro-4(H)-3,1-benzoxazin-2-one-1 1-(4-cyanobenzyl)hydrochloride Step A: 4-(1,2-dihydro-4(H)-3,1 -benzoxazin-2-one-1 1 hydrochloride To a solution of the amine hydrochloride from Step C of Example 26 (135 mg, 0.502 mmol) in 10 mL of 1,2-dichloroethane at 0 °C was added 4A powdered molecular sieves (360 mg), followed by sodium triacetoxyborohydride (168 mg, 0.793 mmol). The imidazole carboxaldehyde from Step E of Example 1 (120 mg, 0.570 mmol) was added, and the reaction was stirred at 0 oC. After 56 hours, the reaction was poured into EtOAc, washed with dilute aq. NaHCO 3 and the WO 97/38665 PCT/US97/06487 157aqueous layer was back-extracted with EtOAc. The combined organics were washed with brine, dried (Na 2

SO

4 filtered, and concentrated in vacuo. The resulting product was taken up in 10 mL of CH 2 C1 2 and propylamine (2 mL) was added. The mixture was stirred for 12 hours, then concentrated in vacuo to afford a pale yellow foam. This material was purified by silica gel chromatography (50-80%% acetone/CH 2 C12), and the resultant white foam was taken up in CH 2 C1 2 and treated with excess equivalents of 1 M HCl/ether solution. After concentrated in vacuo, the product dihydrochloride was isolated as a white powder.

EXAMPLE 28 N- {(4-Cyanobenzyl)-5-imidazolyl} ethyl]-4-carbamoyl- 1phenvlpiperidine hydrochloride 0 N NO NC"H

.N

Step A: 4-Cvanobenzyl-N-phthalovlhistamine NF-Pivaloyloxymethyl-N-phthaloylhistamine (4.55 g, 12.8 mmol) was prepared as previously described C. Emmett, F. H.

Holloway, and J. L. Turner, J. Chem. Soc., Perkin Trans. 1, 1341, (1979)). a-Bromo-p-tolunitrile (3.77 g, 19.2 mmol) was dissolved in acetonitrile (70 mL). The solution was heated at 55 0 C for 4 h, cooled to room temperature, and filtered to remove the white solid. The acetonitrile (30 mL) was concentrated to 1/2 its volume under reduced pressure and the solution was heated at 55 0 C overnight. The solution was cooled and filtered to give a white solid. The volume of the filtrate was reduced to 10 mL, the solution was heated at 55 0 C for 1 hr, then cooled to room temperature, diluted with ethyl acetate (25 mL) and filtered to obtain additional white solid. The solids were combined, WO 97/38665 PCTIUS97/06487 158dried, and dissolved in methanol (100 mL) which was saturated with ammonia gas while the temperature was maintained below 300C. The solution was stirred for 1 hr, concentrated to dryness, and extracted with methylene chloride (3x200 mL), dried (MgSO4), concentrated, and chromatographed (silica gel, 10:90:1 MeOH/CH2CI2/NH 4 0H) to give the title compound StepB: 4-Cvanobenzvl histamine 4 -Cyanobenzyl-Na-phthaloylhistamine (1.64 g, 4.61 mmol), and hydrazine (1.46 mL, 46.1 mmol) were dissolved in absolute ethanol (70 mL). The solution was concentrated after 1 hr and filtered to remove a white precipitate which was washed several times with ethanol. The filtrate was concentrated and the residue was chromatographed (silica gel, 10:90:1 MeOH/CH2Cl2/NH40H) to give the title compound.

Step C: 4-Carbethoxv- 1-phenvlpiperidine A mixture of ethyl isonipecotate (2.00 mL, 12.97 mmol), triphenylbismuth (8.56 g, 19.46 mmol), copper(II)acetate (3.52 g, 19.46 mmol) and triethylamine (2.70 mL, 19.46 mmol) was stirred for 17 h at 0 C in dichloromethane (60 mL). The reaction mixture was adsorbed onto silica gel and eluted with 5% ethyl acetate/hexane. The title compound was obtained as an oil.

Step D: 4-Carboxy- -phenvlpiperidine The product from Step C was dissolved in methanol and aqueous sodium hydroxide added. After 1 h, methanol was removed in vacuo, and the residue partitioned between ethyl acetate and aqueous HC1. The organic layer was washed with saturated brine, and dried over MgSO4. Filtration and concentration provided the title compound.

Step E: 1-( 4 -Cyanobenzyl)-5-imidazolyl }ethyl]-3-carbamoyl- 1 -phenvlpiperidine hydrochloride WO 97/38665 PCTfUS97/06487 159- The product from Step D is dissolved in dimethylformamide. To this solution is added 4 -cyanobenzyl histamine dihydrochloride. EDC HC1, and 1-hydroxybenzotriazole. The pH is adjusted to 7.5 with triethylamine. After 16 h, the reaction is poured into water and extracted with ethyl acetate. The organic phase is washed with saturated brine and dried over magnesium sulfate. The crude product is chromatographed on silica gel and the purified product converted to the hydrochloride salt with HCI in methylene chloride.

The title compound is isolated by removal of solvent.

EXAMPLE 29 1-( 4 -Cyanobenzyl)-5-imidazolyl }ethyl]- -phenylpiperidine hydrochloride

N

NC

/N

N

Step A: 4-Formyl-1 -phenylpiperidine The product from Example 28, Step C is dissolved in THF and cooled to -78C under nitrogen. A solution of diisobutylaluminum hydride (1 eq.) in toluene is added dropwise. After 30 min, the reaction is quenched with saturated sodium potassium tartrate solution. The mixture is extracted with ethyl acetate, and the organic phase washed with saturated brine, and dried over MgSO4. Filtration and concentration provides the title compound Step B: 4-Hydroxvmethvl-1 -triphenvlmethylimidazole To a solution of 4 -(hydroxymethyl)imidazole hydrochloride (35.0 g, 260 mmol) in 250 mL of dry DMF at room temperature is added triethylamine (90.6 mL, 650 mmol). A white WO 97/38665 PCT/US97/06487 160 solid precipitates from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) in 500 mL of DMF is added dropwise. The reaction mixture is stirred for 20 hours, poured over ice, filtered, and washed with ice water. The resulting product is slurried with cold dioxane, filtered, and dried in vacuo to provide the titled product which is sufficiently pure for use in the next step.

Step C: 4-Chloromethvl- -triphenylmethylimidazole The product from Step B is dissolved in chloroform and cooled to 0°C under nitrogen. Thionyl chloride (molar equivalent) is added slowly via syringe. The reaction is stirred for 30 min, and extracted with sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to provide the title compound.

Step D: 4-Diethylphosphonomethyl- -triphenvlmethylimidazole The product from Step C is dissolved in acetonitrile and cooled to 0°C. Triethyl phosphite (1 equivalent) and sodium iodide (1 equivalent) are added, and the reaction stirred at room temperature overnight. The reaction is quenched with ammonium chloride, and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated to provide the title compound.

Step E: 1-(Triphenylmethyl)-4-imidazolyl }ethenyl]-1phenylpiperidine The product from Step D is dissolved in THF and cooled to -78°C under nitrogen. A solution of LDA in THF is added dropwise.

The reaction was stirred at -78C for 1 h, then a solution of 4-formyl-1phenylpiperidine from Step A is added, and the reaction warmed to room temperature overnight. The reaction is quenched with ammonium chloride solution, and extracted with ethyl acetate. The title compound is obtained after chromatography on silica gel.

WO 97/38665 PCT/US97/06487 161 Step F: 1-(Triphenylmethyl)-4-imidazolyl} ethyl]-1phenvlpiperidine The product from Step E is dissolved in methanol and hydrogenated at 60 psi hydrogen with 10% palladium on carbon. When reaction is complete, the catalyst is filtered and the title compound obtained after evaporation of solvent.

Step G: 1-(4-Cyanobenzyl)-5-imidazolyl }ethyl]-1phenylpiperidine hydrochloride The product from Step F is dissolved in acetonitrile and reacted with 4-cyanobenzylbromide (1 equivalent) at room temperature overnight. The reaction is concentrated in vacuo, and the residue dissolved in methanol. The methanol solution is refluxed for 3 h and then concentrated. The residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase is washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The title compound is obtained after purification by silica gel chromatography, and conversion to the dihydrochloride salt.

WO 97/38665 PCT/US97/06487 162 EXAMPLE Preparation of 4- [4-Hydroxymethyl-4-(3-trifluoromethoxybenzyl)piperidine-1-ylmethyljimidazol-1 -vlmethyl} benzonitrile

OH

NC

N

O

C

N OCFs Step A: Preparation of Ethyl N-tert-butoxycarbonylpiperidine-4carboxylate To a cold (0 solution of ethyl isonipecotate (39.5g, 0.251 mol) and triethylamine (38.5 mL, 0.276 mol) in dichloromethane (350 mL), a solution of di-tert-butyl dicarbonate (55.9 g, 0.256 mol) in dichloromethane (50 mL) was added over a period of 30 min. The reacting mixture was stirred at room temp. overnight. The product mixture was washed with aqueous potassium hydrogen sulfate (3 times), and brine (to pH The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound as clear, colorless, viscous oil.

Step B: Preparation of Ethyl N-tert-butoxycarbonyl-4-(3-trifluoromethoxybenzyl)piperidine-4-carboxvlate To a cold (-78 solution of ethyl N-tert-butoxycarbonylpiperidine-4-carboxylate (5.16 g, 20.05 mmol) in anhydrous tetrahydrofuran (60 mL), a solution of sodium bis(trimethylsilyl)amide (28 mL, 1M, 28 mmol) was added over a period of 30 min. The resultant mixture was stirred at -78 °C for 1 h, and 3- (trifluoromethoxy)benzyl bromide (5.90 g, 23.14 mmol) was added.

The reacting mixture was allowed to warm to room temp. and stirred overnight. The product mixture was concentrated, and the residue was partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column WO 97/38665 PCTIUS97/06487 163 chromatography on silica gel eluting with 20% ethyl acetate in hexane.

Collection and concentration of appropriate fractions provided the title compound.

Step C: Preparation of N-tert-butoxycarbonyl-4-(3-trifluoromethoxvbenzvl)-4-hydroxvmethylpiperidine To a slurry of lithium aluminum hydride (585 mg, 15.4 mmol) in anhydrous diethyl ether (100 mL) at 0 a solution of ethyl N-tert-butoxycarbonyl-4-(3-trifluoromethoxybenzyl)piperidine-4carboxylate (5.84 g, 14.0 mmol) in diethyl ether (30 mL) was added dropwise with the temp. of the reacting mixture maintained below The resulting mixture was stirred at 0 °C for 30 min, and quenched with successive addition of water (0.58 mL), 15% aqueous NaOH (0.58 mL), and water (1.74 mL). The resultant slurry was stirred at room temp. for 30 min., and filtered through a small plug of Celite. The filtrate was washed brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title alcohol.

Step D: Preparation of 4-(3-trifluoromethoxybenzyl)-4-hydroxymethylpiperidine hydrochloride salt A solution of N-tert-butoxycarbonyl-4-(3trifluoromethoxy-benzyl)-4-hydroxymethylpiperidine (2.9 g) in dichloromethane (100 mL) at 0 °C was saturated with hydrogen chloride gas. The resultant solution was sealed with a rubber septum and stirred at room temp. for 2.5 h. The product solution was concentrated under vacuum to provide the title compound.

Stp E. Preparation of 4- 4 -Hydroxymethyl-4-(3-trifluoromethoxybenzyl)piperidine- 1 -ylmethyl]imidazol- 1vlmethyl }-benzonitrile A mixture of 4 3 -trifluoromethoxybenzyl)-4-hydroxymethylpiperidine hydrochloride salt (0.62 g, 2.0 mmol), 1-(4-cyano- (0.45 g, 2.0 mmol; Example 1, Step diisopropylethylamine (0.53 mL, 3.04 mmol), anhydrous magnesium sulfate (650 mg), activated molecular sieves 3 A powder WO 97/38665 PCT/US97/06487 164- (750 mg), and anhydrous methanol (6 mL) was stirred at room temp.

overnight. The pH of the mixture was adjusted to -5 with addition of glacial acetic acid. To the mixture, a solution of sodium cyanoborohydride in THF (2.2 mL, 1 M, 2.2 mmol) was added slowly over a period of 8 h with a syringe pump, and stirred at room temp.

overnight. The product mixture was diluted with chloroform, filtered through Celite. The filtrate was washed with aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 5-10% methanol in chloroform gradient. Collection and concentration of appropriate fractions provided the title compound as white solid.

Anal. Calcd for C26H27N402F3-0.38 H20: C, 63.56; H, 5.69; N, 11.40. Found: C, 63.55; H, 5.72; N, 11.46.

EXAMPLE 31 Preparation of 5-[4-Hydroxymethyl-4-( 3 -trifluoromethoxybenzyl)piperidine-1-vlmethyll-2-methylimidazol- 1-vlmethyl }benzonitrile

OH

NC

N

NOCF

3 Step A: Preparation of 1-( 4 carboxvaldehyde To a cold (0 mixture of 4 -formyl-2-methylimidazole (10.0 g, 91 mmol), cesium carbonate (44.4 g, 136 mmol), dimethyl formamide (300 mL) stirred with a mechanical stirred, solid 4cyanobenzyl bromide (18.7 g, 95 mmol) was added slowly over a period of 5 h using an open end plastic syringe and a syringe pump. The resultant mixture was stirred at 0 °C overnight, concentrated under vacuum. The residue was partitioned between water and ethyl acetate.

The organic extract was washed with brine, dried over anhydrous WO 97/38665 PCT/US97/06487 165 sodium sulfate, filtered, and concentrated under vacuum. The crude product was subjected to column chromatography on silica gel eluting with 4% methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound as white solid.

1 H NMR (CDC13 300MHz) 6 9.67 (1H, 7.79 (1H, 7.63 (2H, d, J 8.6 Hz), 7.13 (2H, d, J 8.6 Hz), 5,62 (2H, and 2.42 (3H, s) ppm.

Step B: Preparation of 4- 5-[4-Hydroxymethyl-4-(3-trifluoromethoxybenzyl)piperidine-1 -ylmethyl]-2-methylimidazol- 1vlmethyl Ibenzonitrile The title compound was prepared as white solid using the protocol described in Example 30 Step E, substituting l-(4-cyanowith 1-(4-cyanobenzyl)-2- Anal. Calcd for C27H29N402F3: C, 62.05; H, 5.86; N, 11.24. Found: C, 65.06; H, 5.97; N, 11.51.

EXAMPLE 32 Preparation of 5-[4-Hydroxymethyl-4-(3-trifluoromethylbenzyl)piperidine-1-ylmethvllimidazol-1-vlmethyl }benzonitrile

OH

CF

N

CF

3 The title compound was prepared as white solid according to the procedure described in Example 30, Step B E substituting 3- (trifluoromethoxy)benzyl bromide with 3-trifluoromethylbenzyl bromide in Step B.

Anal. Calcd for C26H27N40F3: C, 66.65; H, 5.81; N, 11.96. Found: C, 66.74; H, 5.73; N, 12.38.

EXAMPLE 33 WO 97/38665 WO 9738665PCTIUS97/06487 166 Preparation of 4-1{5- [4-Hydroxymethyl-4-(3 -trifluoromethylbenzyl)p2iperidine- 1-ylmethyl]-2-methylimidazol- 1-ylmethvl J benzonitrile

OH

NC/

NO

H3~ N

CF

3 The title compound was prepared as white solid according to the procedure described in Example 30, Step B E substituting 3- (trifluoromethoxy)benzyl bromide with 3 -trifluoromethylbenzyl bromide in Step B, and substituting 1-(4-cyanobenzyl)imidazole-5carboxyaldehyde with 1 -(4-cyanobenzyl)-2-methylimidazole-5carboxyaldehyde (Example 3 1, Step A) in Step E.

Anal. Calcd for C27H29N40F3*2.85 TFA: C, 48.64; H, 3.98; N, 6.94.

Found: C, 48.61; H, 4.01; N, 6.91.

EXAMPLE 34 Preparation of 4- {5-[4-Hydroxymethyl-4-(2-trifluoromethylbenzyl)p2iperidine- 1 -vmethyllimidazol- 1 -lmethyl }benzonitrile

OH

N C

NO

N

F

3

C

The title compound was prepared as white solid according to the procedure described in Example 30, Step B E substituting 3-(trifluoromethoxy)benzyl bromide with 2trifluoromethylbenzyl bromide in Step B.

Anal. Calcd for C26H27N40F3-0.30 Et2O: C, 66.57; H, 6.15; N, 11.42. Found: C, 66.21; H, 5.80; N, 11.22.

EXAMPLE WO 97/38665 PCT/US97/06487 167 Preparation of 4- 4 -Hydroxymethyl-4-(2-methylbenzyl)piperidine-1vlmethyllimidazol-l-vlmethvl }benzonitrile trifluoroacetate salt

OH

NC N O- N HaC The title compound was prepared as white solid according to the procedure described in Example 30, Step B E substituting 3- (trifluoromethoxy)benzyl bromide with 2-methylbenzyl bromide in Step B. After column chromatography purification, the final product was dissolved in aqueous TFA and lyophilized.

Anal. Calcd for C26H30N40-0.75 TFA-0.05 H20: C, 51.90; H, 4.54; N, 7.69. Found: C, 51.89; H, 4.52; N, 7.68.

EXAMPLE 36 Preparation of 4- 4 -Hydroxymethyl-4-(3-methylbenzyl)piperidine-1ylmethyllimidazol-1-vlmethvl }benzonitrile

OH

NC

N

CH

3 The title compound was prepared as white solid according to the procedure described in Example 30, Step B E substituting 3- (trifluoromethoxy)benzyl bromide with 3-methylbenzyl bromide in Step B. After column chromatography purification, the final product was triturated in diethyl ether, filtered, and dried under vacuum overnight.

Anal. Calcd for C26H30N40*0.05 Et20*0.25 H20: C, 74.44; H, 7.39; N, 13.25. Found: C, 74.43; H, 7.31; N, 13.13.

EXAMPLE 37 WO 97/38665 PCT/US97/06487 168- Preparation of 4- 4 -Hydroxymethyl-4-(3-methylbenzyl)piperidine-1ylmethyl]-2-methylimidazol-1 -ylmethyl} benzonitrile trifluoroacetate salt

OH

NC

-N

H3C

N

CH

3 The title compound was prepared as white solid according to the procedure described in Example 30, Step B E substituting 3- (trifluoromethoxy)benzyl bromide with 3-methylbenzyl bromide in Step B, and substituting 1-( 4 with 1-( 4 (Example 31, Step A) in Step E. After column chromatography purification, the final product was dissolved in aqueous TFA and lyophilized.

Anal. Calcd for C27H32N40*2.45 TFAI1.1 H20: C, 52.65; H, 5.08; N, 7.70. Found: C, 52.67; H, 5.07; N, 7.79.

EXAMPLE 38 Preparation of 2-[4-Hydroxymethyl-4-(3methylbenzyl)piperidine- 1-yl]-2-oxoethyl }imidazol-1vlmethyl)benzonitrile trifluoroacetate salt O OH NC N NOC N

CH

3 Step A: Preparation of 4-(3-methylbenzyl)-4hvdroxvmethylpiperidine hydrochloride salt The title compound was prepared as white solid according to the procedure described in Example 30, Step B D substituting 3- WO 97/38665 PCT/US97/06487 169- (trifluoromethoxy)benzyl bromide with 3 -methylbenzyl bromide in Step

B.

Step B: Preparation of 2-[4-Hydroxymethyl-4-(3methylbenzyl)-piperidine-1 -yl]-2-oxoethyl imidazol- 1vlmethyl)benzonitrile trifluoroacetate salt A mixture of 4 -(3-methylbenzyl)-4hydroxymethylpiperidine hydrochloride salt (175 mg, 0.52 mmol), 1- 4 -cyanobenzyl)imidazole-5-acetic acid-lithium chloride (142 mg, 0.50 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide*HCl (105 mg, 0.55 mmol), l-hydroxy-7-azabenzotriazole (75 mg, 0.55 mmol), diisopropylethylamine (200 pL, 1.1 mmol) in anhydrous dimethylformamide (2.5 mL) was stirred at room temp. overnight. The resultant mixture was concentrated under vacuum, and the residue was partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase.

Collection and lyophilization of appropriate fractions provided the title compound as white solid.

Anal. Calcd for C27H32N40.1.65 TFA: C, 57.70; H, 5.06; N, 8.88.

Found: C, 57.68; H, 5.20; N, 8.83.

EXAMPLE 39 Preparation of 4- 4 -Hydroxymethyl-4-(3-methylbenzyl)piperidine 1carbonvllimidazol- -vlmethvl benzonitrile 0 OH N

CH

3 The title compound was prepared as white solid according to the procedure described in Example 38, Step A B substituting 1-(4- WO 97/38665 PCT/US97/06487 170acid-lithium chloride with 1-(4acid in Step B. The crude product was purified with column chromatography on silica gel eluting with 2methanol in chloroform.

Anal. Calcd for C26H28N402: C, 72.87; H, 6.59; N, 13.07. Found: C, 72.82; H, 6.67; N, 13.44.

EXAMPLE Preparation of 4- 5-[4-Hydroxymethyl-4-( 2 -methylbenzyl)piperidine-1carbonyllimidazol-1-vlmethyl benzonitrile 0 OH NC N O- N HaC The title compound was prepared as white solid according to the procedure described in Example 38, Step A B substituting 1-(4cyanobenzyl)imidazole-5-acetic acid-lithium chloride with 1-(4acid and 4-(3-methylbenzyl)-4hydroxymethylpiperidine hydrochloride salt with 4-(2-methylbenzyl)-4hydroxymethylpiperidine hydrochloride salt (Example 35) in Step B.

The crude product was purified with column chromatography on silica gel eluting with 2-5% methanol in chloroform.

EXAMPLE 41 Preparation of 4- 5-[4-Hydroxymethyl-4-(3-chlorobenzyl)-piperidine- 1-ylmethyl]-2-methylimidazol-1 -ylmethyl }benzonitrile WO 97/38665 PCT/US97/06487 171

OH

NC'O

C

N H3CC- N N CI The title compound was prepared as white solid according to the procedure described in Example 30, Step B E substituting 3- (trifluoromethoxy)benzyl bromide with 3-chlorobenzyl bromide in Step B, and substituting 1-(4-cyanobenzyl)imidazole-5-carboxyaldehyde with 1-(4-cyanobenzyl)-2-methylimidazole-5-carboxyaldehyde (Example 31, Step A) in Step E.

Anal. Calcd for C26H29N40C*0.20 H20: C, 69.00; H, 6.55; N, 12.38.

Found: C, 68.96; H, 6.78; N, 12.49.

EXAMPLE 42 Preparation of 4- {5-[4-Hydroxymethyl-4-(2-cyanobenzyl)-piperidine- 1ylmethyll-2-methvlimidazol-1 -ylmethyl }benzonitrile N C\N N

H

3 C N NC The title compound was prepared as white solid according to the procedure described in Example 30, Step B E substituting 3- (trifluoromethoxy)benzyl bromide with 2-cyanobenzyl bromide in Step B, and substituting 1-(4-cyanobenzyl)imidazole-5-carboxyaldehyde with 1-(4-cyanobenzyl)-2-methylimidazole-5-carboxyaldehyde (Example 31, Step A) in Step E. After column chromatography purification, the final product was triturated in diethyl ether, filtered, and dried under vacuum overnight.

Anal. Calcd for C27H29N50*0.05 H20*0.05 Et20: C, 73.55; H, 6.72; N, 15.77. Found: C, 73.51; H, 6.55; N, 15.75.

WO 97/38665 PCT/US97/06487 -172- EXAMPLE 43 Preparation of 4- 4 -Hydroxymethyl-4-(3-cyanobenzyl)-piperidine-1ylmethyll-2-methylimidazol- I -vlmethvl Ibenzonitrile

OH

NC

N

H3C N CN The title compound was prepared as white solid according to the procedure described in Example 30, Step B E substituting 3- (trifluoromethoxy)benzyl bromide with 3-cyanobenzyl bromide in Step B, and substituting 1-(4-cyanobenzyl)imidazole-5-carboxyaldehyde with 1-( 4 -cyanobenzyl)-2-methylimidazole-5-carboxyaldehyde (Example 31, Step A) in Step E. After column chromatography purification, the final product was triturated in diethyl ether, filtered, and dried under vacuum overnight.

Anal. Caled for C27H29N50*0.35 H20*0.5 Et20: C, 72.12; H, 7.24; N, 14.50. Found: C, 72.13; H, 6.99; N, 14.47.

EXAMPLE 44 Preparation of 4- 5-[4-Hydroxymethyl-4-( 4 -cyanobenzyl)piperidine-1lmethyll-2-methylimidazol-1-vlmethyl }benzonitrile

OH

NC\ N O Nz C

N

The title compound was prepared as white solid according to the procedure described in Example 30, Step B E substituting 3- (trifluoromethoxy)benzyl bromide with 4-cyanobenzyl bromide in Step B, and substituting 1-( 4 with 1-(4-cyanobenzyl)-2-methylimidazole-5-carboxyaldehyde WO 97/38665 WO 9738665PCTIUS97/06487 173 (Example 3 1, Step A) in Step E. After column chromatography purification, the final product was triturated in diethyl ether, filtered, and dried under vacuum overnight.

Anal. Calcd for C27H29N50*O. 1 H20-0.25 Et2O: C, 73.12; H, 6.95; N, 15.23. Found: C, 73.14; H, 6.83; N, 15.23.

EXAMPLE Preparation of 4-f 5-14-Hydroxymethyl-4-(2,5dimethylbenzyl)piperidine- 1-ylmethyl]-2-methylimidazol- 1vimethyl I benzonitrile OH OH 3 NC

NO

H

3 0 N

H

3 0 The title compound was prepared as white solid according to the procedure described in Example 30, Step B E substituting 3-(trifluoromethoxy)benzyl bromide with dimethylbenzyl bromide in Step B, and substituting 1-(4with 1- (4-cyanobenzyl)-2- (Example 3 1, Step A) in Step B.

Anal. Calcd for C28H34N40*0.1 H20: C, 75.68; H, 7.76; N, 12.61.

Found: C, 75.62; H, 7.65; N, 12.60.

EXAMPLE 46 Preparation of 4-f 5- [4-Hydroxymethyl-4-(2,5dichlorobenzyl)piperidine- 1 -ylmethyl]-2-methylimidazolb. 1ylmethyl Ibenzonitrile OH CI NC NN N C

NCN

H

3 0 N C1 WO 97/38665 PCT/US97/06487 174- The title compound was prepared as white solid according to the procedure described in Example 30, Step B E substituting 3- (trifluoromethoxy)benzyl bromide with 2,5-dichlorobenzyl bromide in Step B, and substituting 1-(4-cyanobenzyl)imidazole-5-carboxyaldehyde with 1-( 4 (Example 31, Step A) in Step E.

Anal. Calcd for C26H28N40C12: C, 64.60; H, 5.84; N, 11.59. Found: C, 65.33; H, 5.70; N, 11.85.

EXAMPLE 47 Preparation of 4- 5-[4-Hydroxymethyl-4-(3,5dimethylbenzyl)piperidine-1 -ylmethyl]-2-methylimidazol-1 ylmethyl I benzonitrile OH

CH

3 NC N

N

HzC N N CH 3 The title compound was prepared as white solid according to the procedure described in Example 30, Step B E substituting 3- (trifluoromethoxy)benzyl bromide with 3,5-dimethylbenzyl bromide in Step B, and substituting 1-( 4 with 1-( 4 (Example 31, Step A) in Step E. After column chromatography purification, the final product was triturated in diethyl ether, filtered, and dried under vacuum overnight.

Anal. Calcd for C28H34N40*0.14 Et20: C, 75.73; H, 7.88; N, 12.37.

Found: C, 75.70; H, 7.88; N, 12.39.

EXAMPLE 48 WO 97/38665 PCT/US97/06487 175 Preparation of {4-Hydroxymethyl-4-[3,5bis(trifluoromethyl)benzyl]-piperidine-1 -ylmethyl} -2-methylimidazol-1ylmethyl)benzonitrile OH

CF

3

HNCCN

H3C 3 N

CF

3 The title compound was prepared as white solid according to the procedure described in Example 30, Step B E substituting 3- (trifluoromethoxy)benzyl bromide with bromide in Step B, and substituting 1-(4-cyanobenzyl)imidazole-5carboxyaldehyde with 1-( 4 carboxyaldehyde (Example 31, Step A) in Step E. After column chromatography purification, the final product was triturated in diethyl ether, filtered, and dried under vacuum overnight.

Anal. Calcd for C28H34N400.14 Et20: C, 61.01; H, 5.42; N, 9.81.

Found: C, 61.01; H, 5.12; N, 9.58.

EXAMPLE 49 Preparation of 4- 5-[4-Hydroxymethyl-4-(2,3dichlorobenzyl)piperidine-1-ylmethyl]-2-methylimidazol-1vlmethyl }benzonitrile

OH

NC

N

H

3 C N CI

CI

The title compound was prepared as white solid according to the procedure described in Example 30, Step B E substituting 3- (trifluoromethoxy)benzyl bromide with 2,3-dichlorobenzyl bromide in Step B, and substituting 1-(4-cyanobenzyl)imidazole-5-carboxyaldehyde WO 97/38665 WO 9738665PCTIUS97/06487 176 with 1- 4 (Example 3 1, Step A) in Step E.

Anal. Calcd for C26H28N4OC1200.2 H20*0.05 MeOH: C, 64.03; H, 5.90; N, 11.47. Found: C, 64.04; H, 5.95; N, 11.75.

EXAMPLE Preparation of 4- 4 -Hydroxymethyl-4-benzylpiperidine-1 -ylmethyl)- 2-methylimidazol- 1 -ylmethyllbenzonitrile

OH

NC\

N

The title compound was prepared as white solid according to the procedure described in Example 30, Step B E substituting 3- (trifluoromethoxy)benzyl bromide with benzyl bromide in Step B, and substituting 1 4 -cyanobenzyl)imidazole-5-carboxyaldehyde with 1 cyanobenzyl)-2-methylimidazole-5-carboxyaldehyde (Example 31, Step A) in Step E.

Anal. Calcd for C26H28N40C12: C, 75.00; H, 7.3 1; N, 13.46. Found: C, 75.06; H, 7.20; N, 13.43.

EXAMPLE 51 Preparation of 4- [4-Hydroxymethyl-4- (3 -trifluoromethoxybenzyl)piperidine- 1-ylmethyl]-2-methylimidazol- 1-ylmethvl }benzamide

H

2 N -ON

OCF

3 WO 97/38665 PCT/US97/06487 177- A solution of 4-{5-[4-hydroxymethyl-4-(3trifluoromethoxy-benzyl)-piperidine-1 -ylmethyl]-2-methylimidazol- 1 ylmethyl}benzonitrile (71 mg, 0.142 mmol; Example 31) and sodium perborate tetrahydrate (92.8 mg, 0.6 mmol) in a mixture of methanol (2.5 mL) and water (1 mL) was heated at 50 "C for 7 h. The resultant mixture was concentrated under vacuum, and the residue was partitioned between chloroform and dilute hydrochloric acid (0.5 M).

The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound as white solid.

Anal. Calcd for C27H31N403F3-0.25 H20: C, 62.24; H, 6.09; N, 10.75. Found: C, 62.20; H, 6.05; N, 11.04.

FAB MS m/e 517 (M+1) EXAMPLE 52 Preparation of 4- {5-[4-Methoxymethyl-4-(3-methylbenzyl)-piperidine- 1-vlmethyllimidazol- -vlmethyl benzonitrile hydrochloride salt NC

N

N OCH3 N

CH

3 Step A: Preparation of N-tert-butoxycarbonyl-4-(3-methylbenzyl)- 4-hvdroxvmethvlpiperidine The title compound was prepared using the protocol described in Example 30, Step A C, substituting 3- (trifluoromethoxy)benzyl bromide with 3-methylbenzyl bromide in Step

B.

Step B: Preparation of N-tert-butoxycarbonyl-4-(3-methylbenzyl)- 4-methoxvmethylpiperidine WO 97/38665 PCT/US97/06487 178 To a suspension of potassium hydride (0.40 g, dry weight, mmol; obtained from washing 0.97 g of 35% potassium hydride dispersion in mineral oil with hexanes and drying under a stream of argon) in anhydrous THF (45 mL), N-tert-butoxycarbonyl-4-(3methylbenzyl)-4-hydroxymethylpiperidine (1.89 g, 5.9 mmol) in THF mL) was added. The resultant mixture was stirred at room temp.

for 1 h, and treated with dimethyl sulfate (1.13 mL, 11.9 mmol). The reacting mixture was stirred at room temp. overnight. The product mixture was cooled to 0 quenched with water, and diluted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum.

The residue was subjected to column chromatography on silica gel eluting with 10% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.

Step C: Preparation of 4 -(3-methylbenzyl)-4-methoxymethylpiperidine hydrochloride salt To a cold (0 solution of N-tert-butoxycarbonyl-4-(3methylbenzyl)-4-methoxymethylpiperidine (1.95 g) in ethyl acetate (100 mL), a stream of anhydrous hydrogen chloride gas was bubbled for min. The resultant mixture was stirred at 0 °C for 1 h, purged with argon for 20 min., and concentrated under vacuum to provide the title compound as white solid.

Step D: Preparation of l-( 4 hydrochloride salt A mixture of I-( 4 (10.8 g, 50.70 mmol; Example 1, Step D) and thionyl chloride (70 mL, 960 mmol) was stirred at room temp. overnight under a calcium chloride drying tube. The resultant mixture was concentrated under vacuum, and residual thionyl chloride was removed by co-evaporation with toluene. The residue was recrystallized from boiling methanol.

After cooling to room temp., the white solid precipitated was obtained WO 97/38665 PCT/US97/06487 179 by filtration, and residual solvent was removed under vacuum overnight.

Step E: Preparation of 4- {5-[4-Methoxymethyl-4-(3-methylbenzyl)piperidine-1 -ylmethyl]imidazol-1 -vlmethyl Ibenzonitrile hydrochloride salt A solution of 4-(3-methylbenzyl)-4methoxymethylpiperidine hydrochloride salt (1.57 g, 5.8 mmol), 1-(4hydrochloride salt (1.57 g, 5.8 mmol), and diisopropylethyl-amine (5.1 mL, 29 mmol) in anhydrous acetonitrile (75 mL) was heated at 60 "C overnight. The resultant mixture was concentrated under vacuum, and the residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 3% methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound as free base. The free base obtained was dissolved in anhydrous diethyl ether (50 mL), cooled to 0 and bubbled with anhydrous hydrogen chloride gas for 20 second. The resultant mixture was concentrated, and the residue solid recrystallized from a mixture of methanol and diethyl ether. The white solid precipitated was filtered, and residual solvent was removed under vacuum overnight to provide the title compound.

Anal. Calcd for C27H32N40*2 HC1-0.70 H20: C, 63.08; H, 6.94; N, 10.90. Found: C, 63.06; H, 6.91; N, 10.95.

EXAMPLE 53 Preparation of 5-[ 4 -Methoxymethyl-4-(3-methylbenzyl)-piperidine- 1-ylmethyll-2-methylimidazol-1-vlmethyl }benzonitrile WO 97/38665 PCT/US97/06487 180

-OCH

3 NC

N

OH

3

H

3 C N

CH

3 Step A: Preparation of 1-( 4 -cyanobenzyl)-5-hydroxymethyl-2methylimidazole A solution of 1-( 4 carboxyaldehyde (4.0 g, 17.76 mmol; Example 31, Step A) in methanol mL) at room temp. was treated with sodium borohydride (0.52 g, 13.7 mmol; added in two portions, 10 min. apart). After stirring at room temp. for 30 min., the resultant slurry was concentrated to about mL. The white solid precipitated was filtered, washed with anhydrous diethyl ether, and residual solvent was removed under vacuum to provide the title compound.

Step B: Preparation of 1-(4-cyanobenzyl)-5-chloromethyl-2methylimidazole hydrochloride salt A mixture of 1-( 4 -cyanobenzyl)-5-hydroxymethyl-2methylimidazole (3.45 g, 15.2 mmol) and thionyl chloride (30 mL, 411 mmol) was stirred at room temp. overnight under a calcium chloride drying tube. The resultant mixture was concentrated under vacuum, and residual thionyl chloride was removed by co-evaporation with toluene. The residue was triturated with anhydrous diethyl ether, filtered, washed with ether to provide the title compound as white solid.

Step C: Preparation of 4- 5 4 -Methoxymethyl-4-(3-methylbenzyl)piperidine-1 -ylmethyl]-2-methylimidazol- 1 -ylmethyl benzonitrile The title compound was prepared using the protocol described in Example 52, Step E substituting 1-(4-cyanobenzyl)-5chloromethyl-imidazole hydrochloride salt with 1-(4-cyanobenzyl)-5chloromethyl-2-methylimidazole hydrochloride salt. After column chromatography purification, collection and concentration of WO 97/38665 WO 9738665PCTIUS97/06487 181 appropriate fractions, the residue was triturated with anhydrous diethyl ether. The white solid precipitated was obtained by filtration and provided the title compound.

Anal. Calcd for C28H34N4000.15 Et2O -0.50 H20: C, 74.24; H, 7.95; N, 12.11. Found: C, 74.22; H, 7.59; N, 12.13.

EXAMPLE 54 Preparation of [4-Methoxymethyl-4- (3 -trifluoromethoxybenzyl).

piperidine- 1-ylmethyllimidazol- 1-ylmethyl }benzonitrile hydrochloride salt 00H 3 NC No N 00F 3 The title compound was prepared using the protocol described in Example 30, Step A C using 3 -(trifluoromethoxy)benzyl bromide in Step B, and in Example 52, Step B E substituting N-tertbutoxycarbonyl- 4 -(3-methylbenzyl)4hydroxymethylpiperidine with Ntert-butoxy-carbonyl-4-(3 -trifluorornethoxybenzyl)-4hydroxymethylpiperidine in Step B.

Anal. Calcd for C27H29N402F3-2.6 HC1: C, 54.66; H, 5.37; N, 9.44.

Found: C, 54.69; H, 5.37; N, 9.42.

EXAMPLE Preparation of 4-1{5- 4 -Methoxymethyl-4-(3-trifluoromethoxybenzyl).

piperidine- 1-ylmethyl]-2-methylimidazol- 1-ylmethyl }benzonitrile hydrochloride salt WO 97/38665 WO 9738665PCTIUS97/06487 -182

OCH

3 NC

NN

H

3 C N

OCF

3 The title compound was prepared using the protocol described in Example 30, Step A C using 3-(trifluoromethoxy)benzyl bromide in Step B, and in Example 52, Step B E substituting N-tertbutoxycarbonyl-4-(3-methylbenzyl)-4-hydroxymethylpiperidine with Ntert-butoxy-carbonyl-4- (3 -trifluoromethoxybenzyl)-4hydroxymethylpiperidine in Step B, and substituting 1 -(4-cyanobenzyl)hydro-chioride salt with 1 -(4-cyanobenzyl)-5 chloromethyl-2-methylimidazole hydrochloride salt in Step E.

Anal. Calcd for C28H3lN402F3.2.2 HCL: C, 56.73; H, 5.65; N, 9.45.

Found: C, 56.79; H, 5.39; N, 9.40.

EXAMPLE 56 Preparation of 4-1{5-[4-Methoxymethyl-4-(2-trifluoromethoxybenzyl)piperidine- 1-ylmethyl] imidazol- 1-ylmethyl }benzonitrile hydrochloride salt

OCH

3 NC\ N D N) N

CF

3 0 The title compound was prepared using the protocol described in Example 30, Step A C using 2-(trifluoromethoxy)benzyl bromide in Step B, and in Example 52, Step B E substituting N-tertbutoxycarbonyl-4-(3 -methylbenzyl)-4-hydroxymethylpiperidine with Ntert-butoxy-carbonyl-4- (2-trifluoromethoxybenzyl)-4hydroxymethylpiperidine in Step B.

Anal. Caled for C27H29N402F3*2.45 HCl*0.20 Et2O: C, 55.40; H, 5.59; N, 9.30. Found: C, 55.38; H, 5.52; N, 9.20.

WO 97/38665 WO 9738665PCT/US97/06487 183 EXAMPLE 57 Preparation of 4- [4-Methoxymethyl-4- (2-trifluoromethoxybenzyl)piperidine- 1-ylmethyl] -2-methylimidazol- 1-ylmethyl Ibenzonitrile hydrochloride salt 00H 3 NC N

H

3 C N

CF

3 0 The title compound was prepared using the protocol described in Example 30, Step A C using 2-(trifluoromethoxy)benzyl bromide in Step B, and in Example 52, Step B E substituting N-tertbutoxycarbonyl-4- (3-methylbenzyl)-4-hydroxymethylpiperidine with Ntert-butoxy-carbonyl-4- (2-trifluoromethoxybenzyl)-4hydroxymethylpiperidine in Step B, and substituting I -(4-cyanobenzyl)dazole hydro-chloride salt with 1- chloromethyl-2-methylimidazole hydrochloride salt in Step E.

Anal. Calcd for C28H31N402F3-2.6 HC1: C, 55.37; H, 5.58; N, 9.22.

Found: C, 55.38; H, 5.52; N, 9.20.

EXAMPLE 58 Preparation of 5-[4-Methoxymethyl-4-(3-cyanobenzyl)-piperidine- 1ylmethyl] -2-methylimidazol- 1-ylmethyl Ibenzonitrile trifluoroacetate salt 00CH 3 WO 97/38665 PCT/US97/06487 184- The title compound was prepared using the protocol described in Example 30, Step A C using 3-cyanobenzyl bromide in Step B, and in Example 52, Step B E substituting N-tertbutoxycarbonyl- 4 3 -methyl-benzyl)-4-hydroxymethylpiperidine with N-tert-butoxycarbonyl-4-( 3 -cyanobenzyl)-4-hydroxymethylpiperidine in Step B, and substituting 1-( 4 hydrochloride salt with 1-( 4 -cyanobenzyl)-5-chloromethyl-2methylimidazole hydrochloride salt in Step E. The crude product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.

Anal. Calcd for C28H31N50*2 TFA: C, 56.39; H, 4.88; N, 10.27.

Found: C, 56.04; H, 5.06; N, 10.26.

EXAMPLE 59 Preparation of 2 4 -Methoxymethyl-4-(3-methylbenzyl)piperidine-1-yl]-2-oxoethyl} imidazol-1 -ylmethyl)benzonitrile trifluoroacetate salt O

OCH

3 NC N N N CH 3 The title compound was prepared according to the procedure described in Example 38, Step B substituting 4-(3methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with 4-(3methylbenzyl)-4-methoxymethylpiperidine hydrochloride salt (Example 52, Step The crude product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase.

Anal. Calcd for C28H32N402-1.7 TFA: C, 57.98; H, 5.22; N, 8.61.

Found: C, 57.93; H, 5.30; N, 8.67.

WO 97/38665 WO 9738665PCTIUS97/06487 -185 EXAMPLE Preparation of 4-1{ -II 4 -Methoxymethyl-4-(3-methylbenzyl)piperidinecarbonyllimidazol- 1-ylmethyl lbenzonitrile trifluoroacetate salt -0

OCH

3 NC

N

OH

3 The title compound was prepared according to the procedure described in Example 38, Step B substituting 4-(3methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with 4- (3methylbenzyl)-4-methoxymethylpiperidine hydrochloride salt (Example 52, Step and 1-( 4 -cyanobenzyl)imidazole-5-acetic acid-lithium chloride with l-( 4 -cyanobenzyl)imidazole-5-carboxylic acid. The crude product was subjected to high pressure liquid column chromatography on C- 18 reverse phase stationary phase. Collection and Ilyophilization of appropriate fractions provided the title compound as white solid.

Anal. Calcd for C27H30N40*1.2 TFA. 1.1 H20: C, 58.93; H, 5.62; N, 9.35. Found: C, 58.90; H, 5.41; N, 9.74.

EXAMPLE 61 Preparation of Methyl 1- (4-cyanobenzyl)-3 H-imidazol-4-ylmethyl]-4- (3 -methvlbenzyl)piperidine-4-carboxylate C0 2

CH

3 NC N

OH

3 Step A: Preparation of Methyl N-tert-butoxycarbonyl-4-(3-methyl.

benzylbpiperidine-4-carboxylate WO 97/38665 PCT/US97/06487 186- To a cold (-78 solution of methyl N-tertbutoxycarbonyl-piperidine-4-carboxylate (5.0 g, 20.5 mmol; Example 3, Step B) in anhydrous THF (70 mL), a solution of sodium bis(trimethylsilyl)amide (20.5 mL, 1M, 20.5 mmol) was added over a period of 30 min. The resultant mixture was stirred at -78 "C for 1 h., and 3-methylbenzyl bromide (2.77 mL, 20.5 mmol) was added. The reacting mixture was allowed to warm up to room temp. and stirred overnight. The product mixture was concentrated, and the residue was partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 10% ethyl acetate in hexane.

Step B: Preparation of Methyl 4-(3-methylbenzyl)piperidine-4carboxvlate hydrochloride salt To a cold (0 solution of methyl N-tert-butoxycarbonyl- 4-(3-methylbenzyl)piperidine-4-carboxylate (1.14 g) in ethyl acetate mL), a stream of anhydrous hydrogen chloride gas was bubbled for min. The resultant mixture was stirred at 0 °C for 1 h, purged with argon for 10 min., and concentrated under vacuum to provide the title compound as white solid.

Step C: Preparation of Methyl 1-[3-(4-cyanobenzyl)-3H-imidazol-4 vlmethvll-4-(3-methylbenzvl)piperidine-4-carboxylate A solution of methyl 4-(3-methylbenzyl)piperidine-4carboxylate hydrochloride salt (142 mg, 0.5 mmol), 1-(4-cyanobenzyl)hydrochloride salt (135 mg, 0.5 mmol; Example 52, Step and diisopropylethylamine (0.26 mL, 1.5 mmol) in anhydrous acetonitrile (5 mL) was heated under reflux overnight.

The resultant mixture was concentrated under vacuum, and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic extract was washed with brine, dried over WO 97/38665 PCT/US97/06487 187anhydrous sodium sulfate, filtered, and concentrated under vacuum.

The residue was subjected to column chromatography on silica gel eluting with 5% methanol in chloroform. After collection and concentration of appropriate fractions, the residue was recrystallized from a mixture of ethyl acetate and hexane to provide the title compound as white solid.

Anal. Calcd for C27H30N402*0.2 Hexane: C, 73.66; H, 7.19; N, 12.18.

Found: C, 73.68; H, 6.84; N, 11.79.

EXAMPLE 62 Preparation of Methyl 1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4- (3-trifluoromethoxvbenzyl)piperidine-4-carboxylate trifluoroacetate salt C0 2

CH

3 NC N o N

OCF

3 The title compound was prepared using the protocol described in Example 61, Step A C substituting 3-methylbenzyl bromide with 3-trifluoromethoxybenzyl bromide in Step A. The final product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.

Anal. Calcd for C27H27N403F3*2.35 TFA -1.05 H20: C, 47.62; H, 3.97; N, 7.01. Found: C, 47.61; H, 4.10; N, 6.61.

EXAMPLE 63 Preparation of Methyl 1-[3-(4-cyanobenzyl)-2-methyl-3H-imidazol-4ylmethyl]-4-(3-trifluoromethoxybenzyl)piperidine-4-carboxylate trifluoroacetate salt WO 97/38665 PCT/US97/06487 188- SC0 2

CH

3 NC

N

H3 N

OCF

3 The title compound was prepared using the protocol described in Example 61, Step A C substituting 3-methylbenzyl bromide with 3-trifluoromethoxybenzyl bromide in Step A, and substituting 1-( 4 -cyano-benzyl)-5-chloromethylimidazole hydrochloride salt with I-(4-cyano-benzyl)-5-chloromethyl-2-methylimidazole hydrochloride salt (Example 53, Step B) in Step C. The final product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.

Anal. Calcd for C28H29N403F3-2.3 TFA *1.05 H20: C, 48.47; H, 4.17; N, 6.94. Found: C, 48.48; H, 4.19; N, 6.91.

EXAMPLE 64 Preparation of Methyl 1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4- (2-trifluoromethoxybenzvl)piperidine-4-carboxylate trifluoroacetate salt

CO

2

CH

3 NC N N

F

3

CO

The title compound was prepared using the protocol described in Example 61, Step A C substituting 3-methylbenzyl bromide with 2-trifluoromethoxybenzyl bromide in Step A. The final product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.

Anal. Calcd for C27H27N403F3-2.50 TFA -2.30 H20: C, 45.81; H, 4.10; N, 6.68. Found: C, 46.11; H, 3.89; N, 6.28.

WO 97/38665 PCT/US97/06487 189- EXAMPLE Preparation of Methyl 4 -cyanobenzyl)-3H-imidazol-4-ylmethyl]-4- 3 -cvanobenzvl)piperidine-4-carboxvlate hydrochloride salt SC0 2

CH

3 NC

N

CN

The title compound was prepared using the protocol described in Example 61, Step A C substituting 3-methylbenzyl bromide with 3-cyanobenzyl bromide in Step A. After column chromatography on silica gel, the free base obtained was dissolved in anhydrous diethyl ether. The ethereal solution was cooled to 0 and bubbled with anhydrous hydrogen chloride gas for 20 second. The resultant mixture was concentrated, and the residue solid recrystallized from a mixture of methanol and diethyl ether. The white solid precipitated was filtered, and residual solvent was removed under vacuum overnight to provide the title compound.

Anal. Calcd for C27H27N502-2.35 HCl-1.80 MeOH: C, 57.95; H, 6.17; N, 11.73. Found: C, 57.94; H, 6.16; N, 11.72.

EXAMPLE 66 Preparation of Methyl 1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4- [3-(benzvloxvcarbonylaminomethyl)benzyvlpiperidine-4-carboxylate C02CH 3 NC

N

N -N 0 WO 97/38665 PCT/US97/06487 190- Step A: Preparation of Methyl N-tert-butoxycarbonyl-4-(3-cyanobenzyl)piperidine-4-carboxvlate The title compound was prepared using the protocol described in Example 61, Step A substituting 3-methylbenzyl bromide with 3-cyanobenzyl bromide.

Step B: Preparation of Methyl N-tert-butoxycarbonyl-4-(3-aminomethylbenzvl)piperidine-4-carboxvlate A mixture of methyl N-tert-butoxycarbonyl-4-(3-cyanobenzyl)piperidine-4-carboxylate (0.6 g, 1.67 mmol), Raney nickel (3 g) in a mixture of ethanol (20 mL) and concentrated aqueous ammonium hydroxide (0.6 mL) was stirred under a balloon of hydrogen gas at room temp. overnight. The slurry was filtered, and the filtrate concentrated under vacuum to provide the title compound.

Step C: Preparation of Methyl N-tert-butoxycarbonyl-4-[3-(benzyloxvcarbonylaminomethyl)benzyllpiperidine-4-carboxylate A mixture of methyl N-tert-butoxycarbonyl-4-(3-aminomethylbenzyl)piperidine-4-carboxylate (1.67 mmol), benzyl chloroformate (0.48 mL, 3.36 mmol), and diisopropylethylamine (1 mL, 5.74 mmol) in dichloromethane was stirred at room temp.. The resultant solution was diluted with dichloromethane, washed with aqueous sodium bicarbonate, and then brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 40% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound as clear colorless gum.

Step D: Preparation of Methyl I-[ 3 4 -cyanobenzyl)-3H-imidazol-4ylmethyl]-4-[3-(benzyloxycarbonylaminomethyl)benzyl]piperidine-4-carboxylate The title compound was prepared using the protocol described in Example 61, Step B C substituting methyl N-tert- WO 97/38665 PCT/US97/06487 191 butoxycarbonyl-4-( 3 -methylbenzyl)piperidine-4-carboxylate with methyl N-tert-butoxycarbonyl-4-[3-(benzyloxycarbonylaminomethyl)benzyl]piperidine-4-carboxylate in Step B. After column chromatography on silica gel, the free base obtained was triturated with a mixture of dichloromethane and diethyl ether. The white solid precipitated was filtered, and residual solvent was removed under vacuum overnight to provide the title compound.

Anal. Calcd for C35H37N504-0.2 Et20O0.05 CH2C12: C, 70.50; H, 6.45; N, 11.47. Found: C, 70.39; H, 6.17; N, 11.46.

EXAMPLE 67 Preparation of Methyl 1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4- [3-(aminomethyl)benzvllpiperidine-4-carboxylate trifluoroacetate salt SC0 2

CH

3 NC N N N NH 2 A mixture of methyl 1-[3-(4-cyanobenzyl)-3H-imidazol-4ylmethyl]-4-[3-(benzyloxycarbonylaminomethyl)benzyl]-piperidine-4carboxylate (0.13 g, 0.22 mmol; Example 66, Step D) and hydrobromide in acetic acid (4 mL) was stirred at room temp. for min. The resultant mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.

Anal. Calcd for C27H31N502-3.35 TFA*1.05 H20: C, 47.15; H, 4.28; N, 8.16. Found: C, 47.15; H, 4.24; N, 8.88.

EXAMPLE 68 WO 97/38665 PCT/US97/06487 192- Preparation of Ethyl 1-[3-(4-cyanobenzyl)-2-methyl-3H-imidazol-4ylmethyl]-4-[3-(methanesulfonylaminomethyl)benzyl]piperidine-4carboxvlate co 2 Et NC

N

H

3 0 N

H

0 S- CH 3

O

Step A: Preparation of Ethyl N-tert-butoxycarbonyl-4-(3-aminomethylbenzvl)piperidine-4-carboxylate The title compound was prepared using the protocol described in Example 66, Step A B substituting methyl N-tertbutoxycarbonyl-piperidine-4-carboxylate with ethyl N-tertbutoxycarbonyl-piperidine-4-carboxylate (Example 30, Step A).

Step B: Preparation of Ethyl N-tert-butoxycarbonyl-4-[3-(methanesulfonvlaminomethyl)benzvll piperidine-4-carboxvylate A mixture of ethyl N-tert-butoxycarbonyl-4-(3-aminomethylbenzyl)piperidine-4-carboxylate (400 mg, 0.106 mmol) and methanesulfonyl chloride (99 pL, 0.127 mmol) in anhydrous pyridine (4 mL) was heated at 70 C for 4 h. The resultant mixture was concentrated, and the residue was subjected to column chromatography on silica gel eluting with 50% ethyl acetate in hexane. Collection and concentration of appropriate fraction provided the title compound.

Step C: Preparation of Ethyl 4 -[3-(methanesulfonylaminomethyl)benzvll piperidine-4-carboxylate hydrochloride salt A solution of ethyl N-tert-butoxycarbonyl-4-[3-(methanesulfonylaminomethyl)benzyl]piperidine-4-carboxylate (270 mg) in dichloromethane (40 mL) at 0 "C was saturated with hydrogen chloride gas. The resultant solution was sealed with a rubber septum and stirred WO 97/38665 PCT/US97/06487 193at room temp. for 2.5 h. The product solution was concentrated under vacuum to provide the title compound Step D: Preparation of Ethyl 1-[3-(4-cyanobenzyl)-2-methyl-3Himidazol-4-ylmethyl]-4-[3-(methanesulfonylaminomethyl)benzyllpiperidine-4-carboxvlate The title compound was prepared using the protocol described in Example 61, Step C substituting methyl 4-(3methylbenzyl)piperidine-4-carboxylate hydrochloride salt with ethyl 4- [3-(methanesulfonylamino-methyl)benzyl]piperidine-4-carboxylate hydrochloride salt, and 1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt with 1-(4-cyanobenzyl)-5-chloromethyl-2methylimidazole hydrochloride salt (Example 53, Step After column chromatography on silica gel, the free base obtained was triturated with anhydrous diethyl ether. The white solid precipitated was filtered, and residual solvent was removed under vacuum overnight to provide the title compound.

Anal. Calcd for C30H37N504 OS-0.2 Et20*0.3 H20: C, 63.35; H, 6.84; N, 11.99. Found: C, 63.34; H, 6.71; N, 11.99.

EXAMPLE 69 Preparation of Ethyl 1-[3-(4-cyanobenzyl)-2-methyl-3H-imidazol-4ylmethyll-4-(3-nitrobenzyl)piperidine-4-carboxvlate N C N_ C02Et

CO

2 Et NC N

N

N NO, Step A: Preparation of Ethyl N-tert-butoxycarbonyl-4-(3nitrobenzyl)piperidine-4-carboxvlate The title compound was prepared using the protocol described in Example 61, Step A substituting methyl N-tertbutoxycarbonyl-piperidine-4-carboxylate with ethyl N-tert- WO 97/38665 WO 9738665PCT/US97/06487 194 butoxycarbonyl-piperidine-4-carboxylate (Example 30, Step and 3methylbenzyl bromide with 3-nitrobenzyl bromide.

Step B: Preparation of Ethyl 1- (4-cyanobenzyl)-2-methyl- 3Himidazol-4-ylmethyl] (3 -nitrobenzyl)piperidine-4carboxylate The title compound was prepared using the protocol described in Example 61, Step B C substituting methyl N-tertbutoxycarbonyl-4-(3 -methylbenzyl)piperidine-4-carboxylate with ethyl N- tert-butoxycarbonyl-4- (3 nitrobenzyl)piperidine-4- carboxyl ate in Step B, and 1- (4-cyano-benzyl)-5-chloromethylimidazole hydrochloride salt with 1- (4-cyano-benzyl)-5-chloromethyl-2-methylimidazole hydrochloride salt (Example 53, Step B) in Step C.

Anal. Calcd for C28H131N504-0.45 CHC13: C, 61.54; H, 5.71; N, 12.61. Found: 61.39; H, 5.56; N, 12.74.

EXAMPLE Preparation of Ethyl 1- [3-(4-cyanobenzyl)-2-rnethyl- 3H-imidazol-4ylmethyl] -4-(3-methanesulfonvlaminobenzvl)p2iperidine-4-carboxvlate

CO

2 Et NC/ No

H

3 C 41N N N-S-OH 3 H"1 0 Step A: Preparation of Ethyl N-tert-butox ycarbonyl-4- (3-methanesulfonylaminobenzyl'piperidine-4-carboxylate A mixture of ethyl N-tert-butoxycarbonyl-4-(3nitrobenzyl)-piperidine-4-carboxylate (0.85 g, 2.17 mmol; Example 69, Step A) and 5% palladium on charcoal (0.06 g) in ethanol (100 mL) was hydrogenated at room temp. at 50 psi overnight. The resultant mixture was filtered through a plug of Celite, and the filtrate was concentrated under vacuum. The residue was dissolved in pyridine (5 mL), treated WO 97/38665 PCT/US97/06487 195 with methanesulfonyl chloride (0.24 mL, 3.2 mmol), and heated at "C for 3 h. The product mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluting with 2% methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound.

Step B: Preparation of Ethyl 1-[3-(4-cyanobenzyl)-2-methyl-3Himidazol-4-ylmethyl]-4-(3-methanesulfonylaminobenzyl)piperidine-4-carboxvlate The title compound was prepared using the protocol described in Example 69, Step B substituting ethyl N-tertbutoxycarbonyl-4-(3-nitrobenzyl)piperidine-4-carboxylate with ethyl Ntert-butoxycarbonyl-4-(3-methanesulfonylaminobenzyl)piperidine-4carboxylate.

Anal. Calcd for C29H35N504S-0.05 CHC13: C, 62.79; H, 6.36; N, 12.60. Found: 62.87; H, 6.24; N, 12.76.

EXAMPLE 71 Preparation of Ethyl 1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4benzvlpiperidine-4-carboxylate

CO

2 Et NC N

N

The title compound was prepared using the protocol described in Example 61, Step A C substituting methyl N-tertbutoxycarbonyl-piperidine-4-carboxylate with ethyl N-tertbutoxycarbonyl-piperidine-4-carboxylate, and 3-methylbenzyl bromide with benzyl bromide.

Anal. Calcd for C27H30N402*0.1 CHC13-0.1 H20: C, 71.33; H, 6.69; N, 12.28. Found: 71.35; H, 6.62; N, 12.40.

WO 97/38665 WO 9738665PCTIUS97/06487 196 EXAMPLE 72 Preparation of methyl 1- 3 4 -cyanobenzyl)-3H-imidazol-4-ylmethyl] -4cyclopropylmethylpip1eridine-4-carboxylate 00 2 0H 3 NC/

N=

N

The title compound was prepared using the protocol described in Example 61, Step A C substituting 3-methylbenzyl bromide with cyclopropylmnethyl bromide.

Anal. Calcd for C23H28N402: C, 70.38; H, 7.19; N, 14.27. Found: 70.41; H, 7.13; N, 14.28.

EXAMPLE 73 Preparation of methyl 1- [3-(4-cyanobenzyl)- 3H-imidazol-4-ylcarbonyl] 4-(3-methylbenzyl)piperidine-4-carboxylate o 00 2

CH

3 N

OH

3 The title compound was prepared according to the procedure described in Example 38, Step B substituting 4-(3methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with methyl 4- (3 -methylbenzyl)piperidine-4-carboxylate hydrochloride salt (Example 61, Step and I -(4-cyanobenzyl)imidazole-5 -acetic acid-lithium chloride with 4 acid.

Anal. Calcd for C27H28N403: C, 71.03; H, 6.18; N, 12.27. Found: C, 71.10; H, 6.27; N, 12.26.

WO 97/38665 PCT1US97/06487 197 EXAMPLE 74 Preparation of methyl 1 -13 4 -cyanobenzyl)- 3 H-imi dazol-4-ylcarbonyl] 4-(2-methx'lbenzyl)p2iperidine-4-carboxylate NC

N

H

3 0 The title compound was prepared according to the procedure described in Example 73, using methyl 4-(2methylbenzyl)piperidine-4-carboxylate hydrochloride salt (Example 61).

Anal. Calcd for C27H28N403.0.05 Et2O: C, 70.98; H, 6.24; N, 12.17.

Found: C, 71.08; H, 6.62; N, 12.49.

EXAMPLE Preparation of methyl 1 -13 -(4-cyanobenzyl H-imidazol-4-ylacetylj -4- 3 -trifluoromethoxybenzyl)piperidine-4-.carboxylate o 0 2

CH

3 NC

N

N 00F 3 The title compound was prepared using the protocol described in Example 61, Step A B substituting 3 -methylbenzyl bromide with 3-trifluoromethoxybenzyl bromide in Step A, and in Example 38, Step B substituting 4-(3-methylbenzyl)-4hydroxymethylpiperidine hydrochloride salt with methyl 4-(3trifluoromethoxybenzyl)piperidine-4-carboxylate hydrochloride salt.

The final product was subjected to high pressure liquid column WO 97/38665 WO 9738665PCT/US97/06487 198 chromatography on C- 18 reverse phase stationary phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.

Anal. Calcd for C28H427N404F3-1.2 TFA* 1.0 H20: C, 52.50; H, 4.38; N, 8.06. Found: C, 52.51; H, 4.41; N, 7.99.

EXAMPLE 76 Preparation of methyl 1 (4-cyanobenzyl)-3 H-imidazol-4-ylacetyl] -4- 2 -trifluoromethoxybenzvl~iperidine-4-carboxylate 0 00 2

CH

3 NC N- N F 3 C0 The title compound was prepared according to the procedure described in Example 75, using 3-trifluoromethoxybenzyl bromide.

Anal. Caled for C28H27N404F3'1.5 TFA-l.7 H20: C, 50.16; H, 4.33; N, 7.55. Found: C, 50.20; H, 4.35; N, 7.38.

EXAMPLE 77 Preparation of methyl 1- [3 4 -cyanobenzyl)-3H-imidazol-4-ylacetyl] -4- (3 -cyanobenzv)p2iperidine-4-carboxylate 0 C0 2

CH

3 NC N o! N ON The title compound was prepared according to the procedure described in Example 75, using 3-cyanobenzyl bromide.

WO 97/38665 PCT/US97/06487 199- Anal. Calcd for C28H27N503-1.9 HC1-0.6 toluene: C, 63.80; H, 5.60; N, 11.56. Found: C, 63.83; H, 5.91; N, 11.57.

EXAMPLE 78 Preparation of methyl 1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylethyl]-4- (3-methylbenzyl)piperidine-4-carboxvlate C0 2

CH

3 NC N N CH 3 To a cold (-78 solution of 3-(4-cyanobenzyl)-3Himidazol-4-ylethyl alcohol (184 mg, 0.81 mmol) and diisopropylethylamine (155 gL, 0.89 mmol) in dichloromethane (3.8 mL), trifluoromethanesulfonic anhydride (143 pL, 0.85 mmol) was added. The resulting mixture was stirred at -78 °C for 20 min., and was treated with a solution of methyl 4-(3-methylbenzyl)piperidine-4carboxylate hydrochloride salt (276 mg, 0.97 mmol; Example 61, Step B) and diisopropylethylamine (186 VL, 1.07 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at -78 °C for one and at room temp. for two h. The resultant solution was concentrated under vacuum, and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.

Anal. Calcd for C28H32N402*2.75 TFA: C, 52.25; H, 4.55; N, 7.27.

Found: C, 52.28; H, 4.66; N, 7.24.

EXAMPLE 79 WO 97/38665 PCT/US97/06487 -200- Preparation of Methyl 2-(n-butyl)-l-[3-(4-cyanobenzyl)-3Himidazol-4-ylmethyl]-4-(3-methylbenzyl)piperidine-4-carboxylate trifluoroacetate salt

SCO

2

CH

3 NC N N

CH

3 Step A: Preparation of Methyl 2-(n-but-1-ynyl)pyridine-4carboxylate A mixture of methyl 2-chloropyridine-4-carboxylate (3.32 g, 19.3 mmol), bis(triphenylphosphine)palladium(II) chloride (0.82 g, 1.1 mmol), copper(I) iodide (0.36 g, 1.9 mmol), triethylamine (30 mL), and n-but-1-yne g) was heated in a sealed tube at 80 °C overnight.

The product mixture was concentrated, and the residue was subjected to column chromatography on silica gel eluting with chloroform.

Step B: Preparation of Methyl N-tert-butoxycarbonyl-2-(n-butyl)piperidine-4-carboxylate A mixture of methyl 2-(n-but-1-ynyl)pyridine-4carboxylate (3.0 g, 15.8 mmol) and platinum (IV) oxide (0.3 g) in methanol (300 mL) acidified with anhydrous hydrochloride gas was hydrogenated at room temp. at 55 psi overnight. The resultant mixture was filtered through a plug of Celite, and the filtrate was concentrated under vacuum. The residue was dissolved in mixture of diisopropylethylamine (6.9 mL, 39 mmol) and dichloromethane mL), and treated with di-tert-butyl dicarbonate (4.1g, 19 mmol). The reaction mixture was stirred at room temp. overnight. The product mixture was concentrated and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract WO 97/38665 PCT/US97/06487 -201 was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 15% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.

Step C: Preparation of Methyl 2-(n-butyl)-l-[3-(4cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-(3methylbenzyl)piperidine-4-carboxvlate trifluoroacetate salt The title compound was prepared using the protocol described in Example 61, Step A C substituting methyl N-tertbutoxycarbonyl-piperidine-4-carboxylate with methyl N-tertbutoxycarbonyl-2-(n-butyl)-piperidine-4-carboxylate in Step A. The final product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.

Anal. Calcd for C31H38N402-2.25 TFA *0.95 H20: C, 55.21; H, 5.50; N, 7.25. Found: C, 55.21; H, 5.52; N, 7.44.

EXAMPLE 81 Preparation of 1-[3-(4-Cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-(3methylbenzyl)isonipecotamide

CONH

2 NCN No N

CH

3 Step A: Preparation of N-tert-butoxycarbonvlisonipecotic acid To a solution of isonipecotic acid (25.8 g, 200 mmol) in 1 M aqueous sodium hydroxide (223 mL, 223 mmol), a solution of ditert-butyl dicarbonate in tetrahydrofuran (200 mL) was added over a period of one h. The resulting solution was stirred at room temp.

WO 97/38665 PCT/US97/06487 -202overnight. The reaction mixture was concentrated under vacuum. The residual aqueous solution was washed with hexane. The combined organic extract was back extracted with saturated aqueous sodium bicarbonate. The basic aqueous extracts were combined, cooled to 0°C, and acidified with 15% aqueous potassium hydrogen sulfate to a pH of The resulting thick slurry was extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to afford the title compound as white solid.

Step B: Preparation of Benzyl N-tert-butoxycarbonvlisonipecotate A mixture of N-tert-butoxycarbonylisonipecotic acid (12.0 g, 52.3 mmol), benzyl alcohol (6.0 mL, 58 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.04 g, 57.6 mmol), and 4-dimethylaminopyridine (642 mg, 5.25 mmol) in anhydrous dichloromethane (100 mL) was stirred at room temp. for 6 h. The resultant mixture was diluted with dichloromethane and washed successively with water, 10% aqueous citric acid, saturated sodium bicarbonate, and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentration under vacuum. The residual oil was subjected to column chromatography on silica eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions afforded the title product as white solid.

Step C: Preparation of Benzyl N-tert-butoxycarbonyl-4-(3-methylbenzyl)isonipecotate To a cold (-78 solution of benzyl N-tertbutoxycarbonyl-isonipecotate (8.02 g, 25.11 mmol) in anhydrous THF mL), a solution of sodium bis(trimethysilyl)amide (35 mL, mmol; 1 M) in THF was added over a period of 10 min. The resulting orange solution was stirred at -78 °C for 1 h. and then treated dropwise with 3-methylbenzyl bromide (4.1 mL, 30.6 mmol). The reaction mixture was allowed to warm to room temp., and stirred overnight.

The reaction was quenched with saturated aqueous ammonium chloride, WO 97/38665 PCT/US97/06487 -203diluted with water, and extracted with ethyl acetate. The organic extracts were combined, washed with brine, and concentrated under vacuum. The residual oil was subjected to column chromatography on silica eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title product.

Step D: Preparation of N-tert-Butoxycarbonyl-4-(3-methylbenzyl)isonipecotic acid A mixture of benzyl N-t-butoxycarbonyl-4-(3methylbenzyl)-isonipecotate (2.36 g, 5.57 mmol), 5% palladium on charcoal (250 mg), and glacial acetic acid (3 mL) in methanol (75 mL), was hydrogenated at 50 psi. in a Parr shaker at room temp. overnight.

The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to provide the title product as white solid.

Step E: Preparation of N-tert-butoxycarbonyl-4-(3-methylbenzyl)isonipecotamide A mixture of N-tert-butoxycarbonyl-4-(3-methylbenzyl)isonipecotic acid (1.02 g, 3.00 mmol), 1-( 3 -dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (0.64 g. 3.36 mmol), 1-hydroxybenzotriazole hydrate (0.45 g, 3.31 mmol), ammonium chloride (0.33 g, 6.15 mmol), and diisopropylethylamine (1.15 mL, 6.60 mmol) in anhydrous dimethylformamide (10 ml) was stirred at room temp.

overnight. The resultant solution was concentrated under vacuum and the residue was partitioned between ethyl acetate and water. The organic extracts were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum.

The residual oil was subjected to column chromatography on silica eluting with 40% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title product.

Step F: Preparation of 4 3 -methylbenzyl)isonipecotamide hydrochloride salt WO 97/38665 PCT/US97/06487 -204- To a cold (0 solution of N-tert-butoxycarbonyl-4-(3methylbenzyl)isonipecotamide (700 mg) in ethyl acetate (50 mL), a stream of anhydrous hydrogen chloride gas was bubbled for 20 min.

The resultant mixture was stirred at 0 °C for 1.5 h, purged with argon for 10 min., and concentrated under vacuum to provide the title compound as white solid.

Step G: Preparation of 1-[3-(4-Cyanobenzyl)-3H-imidazol-4vlmethyll-4-(3-methylbenzvl)isonipecotamide A solution of 4 -(3-methylbenzyl)isonipecotamide hydrochloride salt (134 mg, 0.5 mmol), 1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt (134 mg, 0.5 mmol; Example 52, Step D), and diisopropylethylamine (440 mL, 2.5 mmol) in anhydrous acetonitrile (5 mL) was heated under reflux overnight. The resultant mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 2% methanol in chloroform saturated with ammonia gas. After collection and concentration of appropriate fractions, the residue was triturated with anhydrous diethyl ether. The white solid precipitated was filtered to provide the title compound.

Anal. Calcd for C26H29N50: C, 70.67; H, 6.67; N, 15.19. Found: C, 70.72; H, 6.54; N, 15.48.

EXAMPLE 82 Preparation of 1-[3-(4-Cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-(2methylbenzyl)isonipecotamide

CONH

2 NCN N

H

N

H

3

C

WO 97/38665 PCTUS97/06487 -205- The title compound was prepared using the protocol described in Example 81, Step A G substituting 3-methylbenzyl bromide with 2-methylbenzyl bromide in Step C.

Anal. Calcd for C26H29N50*0.10 CH2Cl2*0.10 Et20: C, 71.77; H, 6.86; N, 15.79. Found: C, 71.64; H, 6.70; N, 15.78.

EXAMPLE 83 Preparation of 4 -Cyanobenzyl)-3H-imidazol-4-ylacetyl]-4-(3methvl-benzvl)isonipecotamide O

CONH

2 NC N

N

CH

3 The title compound was prepared using the protocol described in Example 81, Step A F, and in Example 38, Step B substituting 4-(3-methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with 4 3 -methylbenzyl)isonipecotamide hydrochloride salt. Trituration of the purified product with a mixture of dichloromethane and toluene provided the title compound as white solid.

Anal. Calcd for C27H29N502*0.35 EtOAc*0.05 toluene: C, 70.32; H, 6.61; N, 14.26. Found: C, 70.24; H, 6.59; N, 14.21.

EXAMPLE 84 Preparation of 1-[3-(4-Cyanobenzyl)-3H-imidazol-4-ylacetyl]-4-(2methyl-benzvli sonipecotamide oNC NH 2 NC NO :H l~a \2

H

3

C

WO 97/38665 PCT/US97/06487 -206- The title compound was prepared using the protocol described in Example 82, and in Example 38, Step B substituting 4-(3methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with 4-(2methylbenzyl)-isonipecotamide hydrochloride salt. Trituration of the purified product with a mixture of dichloromethane and toluene provided the title compound as white solid.

Anal. Calcd for C27H29N502-0.20 CH2C12-0.30 toluene: C, 70.35; H, 6.41; N, 14.00. Found: C, 70.26; H, 6.66; N, 13.88.

EXAMPLE Preparation of 1-[ 3 4 -Cyanobenzyl)-3H-imidazol-4-ylcarbonyl]-4-(3methvl-benzvl)isonipecotamide 0

CONH

2 NC

N

CH

3 The title compound was prepared using the protocol described in Example 81, and in Example 39, substituting 4-(3methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with 4-(3methylbenzyl)-isonipecotamide hydrochloride salt. Trituration of the purified product with a mixture of dichloromethane and toluene provided the title compound as white solid.

Anal. Calcd for C26H27N502*0.20 CH2C12-0.20 toluene: C, 69.50; H, 6.13; N, 14.68. Found: C, 69.58; H, 6.32; N, 14.62.

EXAMPLE 86 Preparation of 1-[ 3 4 -Cyanobenzyl)-3H-imidazol- 4 -ylcarbonyl]-4-(2methyl-benzyl)isonipecotamide WO 97/38665 PCT/US97/06487 -207- 0

CONH

2 NC

N

N HaC The title compound was prepared using the protocol described in Example 82, and in Example 39, substituting 4-(3methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with 4-(2methylbenzyl)-isonipecotamide hydrochloride salt. Trituration of the purified product with a mixture of dichloromethane and toluene provided the title compound as white solid.

Anal. Calcd for C26H27N502-0.05 toluene: C, 70.93; H, 6.19; N, 15.70. Found: C, 70.93; H, 6.14; N, 15.73.

EXAMPLE 87 Preparation of 4 -Cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-(3methylbenzvl)piperidine-4-carbonitrile

N

CH

3 Step A: Preparation of N-tert-butoxvcarbonyl-4-hydroxvpiperidine To a solution of 4 -hydroxypiperidine (22.9 g, 226.4 mmol), triethylamine (33 mL, 242 mmol) in dichloromethane (250 mL), a solution of di-tert-butyl dicarbonate in dichloromethane (100 mL) was added over a period of over 1 h. The resulting solution was stirred at room temp. overnight. The reaction mixture was washed with aqueous potassium hydrogen sulfate, and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to afford the title compound.

WO 97/38665 PCT/US97/06487 -208- Step B: Preparation of N-tert-butoxycarbonylpiperidine-4carbonitrile To a cold (0 solution of N-tert-butoxycarbonyl-4hydroxypiperidine (1226.4 mmol) and pyridine (24.3 mL, 300 mmol) in anhydrous dichloromethane (300 mL), methanesulfonyl chloride (17.8 mL, 230 mmol) was added. The reaction mixture was stirred at room temp. overnight. The resultant mixture was diluted with dichloromethane and washed successively with 10% aqueous citric acid, saturated aqueous sodium bicarbonate, and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentration under vacuum. The residue was dissolved in a mixture of potassium cyanide (29 g, 445 mmol) and anhydrous dimethylformamide (800 mL). The reaction mxiture was heated at 100 °C overnight. The resultant slurry was filtered through a plug of Celite, and the filtrate concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 0-10% ethyl acetate in chloroform gradient. Collection and concentration of appropriate fractions provided the title nitrile.

Step C: Preparation of N-tert-butoxycarbonyl-4-(3-methylbenzvl)piperidine-4-carbonitrile To a cold (-78 solution of N-tert-butoxycarbonylpiperidine-4-carbonitrile (4.01 g, 19.08 mmol) in anhydrous THF mL), a solution of sodium bis(trimethysilyl)amide (20 mL, 20 mmol; 1 M) in THF was added over a period of 8 min. The resultant black solution was stirred at -78 "C for 1 h. and treated dropwise with 3methylbenzyl bromide (3.08 mL, 22.8 mmol). The reaction mixture was allowed to warm to room temp., and stirred overnight. The product mixture was quenched with saturated aqueous ammonium chloride, diluted with water, and extracted with ethyl acetate. The organic extracts were combined, washed with brine, and concentrated under vacuum. The residual oil was subjected to column chromatography on silica eluting with 20% ethyl acetate in hexane.

WO 97/38665 PCT/US97/06487 -209- Collection and concentration of appropriate fractions provided the title product.

Step D: Preparation of 4 3 -methylbenzyl)piperidine-4-carbonitrile hydrochloride salt To a cold (0 solution of N-tert-butoxycarbonyl-4-(3methylbenzyl)piperidine-4-carbonitrile (1.60 g, 5.1 mmol) in ethyl acetate (100 mL), a stream of anhydrous hydrogen chloride gas was bubbled for 5 min. The resultant mixture was stirred at 0 °C for minute, purged with argon for 10 min., and concentrated under vacuum to provide the title compound as white solid.

Step E: Preparation of 1-[3-(4-Cyanobenzyl)-3H-imidazol-4vlmethyll-4-(3-methvlbenzvl)piperidine-4-carbonitrile A solution of 4-(3-methylbenzyl)piperidine-4-carbonitrile hydrochloride salt (129 mg, 0.51 mmol), 1-( 4 methylimidazole hydrochloride salt (135 mg, 0.51 mmol; Example 52, Step and diisopropylethylamine (440 mL, 2.5 mmol) in anhydrous acetonitrile (5 mL) was heated under reflux overnight. The resultant mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 85:15 v/v mixture of chloroform saturated with ammonia gas and hexane. After collection and concentration of appropriate fractions, the residue was triturated with a mixture of ethyl acetate and diethyl ether. The white solid precipitated was filtered to provide the title compound.

Anal. Calcd for C26H27N5-0.10 Et20: C, 76.04; H, 6.77; N, 16.80.

Found: C, 76.08; H, 6.80; N, 16.91.

EXAMPLE 88 Preparation of 1-[3-(4-Cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-(2methvlbenzvl)piperidine-4-carbonitrile WO 97/38665 PCTIUS97/06487 210 The title compound was prepared using the protocol described in Example 87, Step A E substituting 3-methylbenzyl bromide with 2-methylbenzyl bromide in Step C.

Anal. Calcd for C26H27N5: C, 76.25; H, 6.65; N, 17. 10. Found: C, 76.23; H, 6.79; N, 17.05.

EXAMPLE 89 Preparation of 1- [3 4 -Cyanobenzyl)-3H-imidazol.4-ylmethyl] 4-(4methvlbenzyl)Diperidine-4-carbonitrile

NC\I

The title compound was prepared using the protocol described in Example 87, Step A E substituting 3-methylbenzyl bromide with 4-methylbenzyl bromide in Step C.

Anal. Calcd for C26H27N5-0.15 CH2Cl2*0.15 H20: C, 73.90; H, 6.55; N, 16.48. Found: C, 73.86; H, 6.22; N, 17.26.

EXAMPLE Preparation of 1- [3 4 -Cyanobenzyl)-2-methyl-3H-imidazol4-.

ylmethyl] (3 -methylbenzyl)piperidine-4-carbonitrile trifluoro acetate salt WO 97/38665 PCT/US97/06487 211

HCN

NC

N

N-

H

3 C N

CH

3 The title compound was prepared using the protocol described in Example 87, Step A E substituting 1-( 4 chloro-methylimidazole hydrochloride salt with 1-( 4 chloro-methyl-2-methylimidazole hydrochloride salt (Example 53, Step B) in Step E. The final product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase.

Anal. Calcd for C27H29N5*2.25 TFA -1.55 H20: C, 53.43; H, 4.89; N, 9.89. Found: C, 53.39; H, 4.87; N, 10.04.

EXAMPLE 91 Preparation of 1-[ 3 4 -Cyanobenzyl)-3H-imidazol-4-ylcarbonyl]-4-(3methylbenzvl)piperidine-4-carbonitrile

OCN

NC

N

CH

3 The title compound was prepared using the protocol described in Example 87, Step A D, and in Example 39 substituting 4- 3 -methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with 4- (3-methylbenzyl)piperidine-4-carbonitrile hydrochloride salt (Example 87, Step D).

Anal. Calcd for C26H25N50-0.15Et20: C, 73.50; H, 6.15; N, 16.11.

Found: C, 73.55; H, 6.15; N, 16.17.

EXAMPLE 92 WO 97/38665 PCT/US97/06487 -212- Preparation of 1-[ 3 -(4-Cyanobenzyl)-3H-imidazol-4-ylcarbonyl]-4-(2methylbenzvl)piperidine-4-carbonitrile O CN NC N

N

H

3

C

The title compound was prepared using the protocol described in Example 87, Step A D, substituting 3-methylbenzyl bromide with 2-methylbenzyl bromide in Step C, and in Example 39 substituting 4-( 3 -methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with 4 2 -methylbenzyl)piperidine-4-carbonitrile hydrochloride salt.

Anal. Calcd for C26H25N500.O10Et20: C, 73.58; H, 6.08; N, 16.25.

Found: C, 73.67; H, 6.18; N, 16.25.

EXAMPLE 93 Preparation of 4 -Cyanobenzyl)-3H-imidazol-4-ylacetyl]-4-(3methvlbenzvl)piperidine-4-carbonitrile trifluoroacetate salt 0 CN NC N N

CH

3 The title compound was prepared using the protocol described in Example 87, Step A D, and in Example 38 substituting 4- 3 -methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with 4- (3-methylbenzyl)piperidine-4-carbonitrile hydrochloride salt (Example 87, Step The final product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase.

WO 97/38665 WO 9738665PCTfUS97/06487 213 Collection and lyophilization of appropriate fractions provided the title compound as white solid.

Anal. Calcd for C27H27N50* 1.6 TFA*0.75 H20: C, 57.25; H, 4.79; N, 11.06. Found: C, 57.26; H, 4.75; N, 11.24.

EXAMPLE 94 Preparation of 1 4 -Cyanobenzyl)-3H-imidazol-4-ylacetyl] methylbenzyl')pip~eridine-4-carbonitrile 0 ON

N

NC N N FI 3

C

The title compound was prepared using the protocol described in Example 87, Step A D, substituting 3-methylbenzyl bromide with 2-methylbenzyl bromide in Step C, and in Example 38 substituting 4 3 -methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with 4 2 -methylbenzyl)piperidine-4-carbonitrile hydrochloride salt.

Anal. Calcd for C27H27N50-0.05 EtOAc*0. 15 Et2O: C, 73.69; H, 6.43; N, 15.46. Found: C, 73.71; H, 6.51; N, 15.53.

EXAMPLE Preparation of 1- (4-Cyanobenzyl)-3 H-imidazol-4-ylethyl] methvlbenzyl)p1iperidine-4-carbonitrile trifluoroacetate salt

ON

NC

NCC

\N/

(IN

OH

3 WO 97/38665 PCT/US97/06487 -214- The title compound was prepared using the protocol described in Example 87, Step A D, and in Example 78 substituting methyl 4-(3-methylbenzyl)piperidine-4-carboxylate hydrochloride salt with 4-(3-methyl-benzyl)piperidine-4-carbonitrile hydrochloride salt (Example 87, Step The final product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase.

Anal. Calcd for C27H29N5-2.6 TFA-0.04 H20: C, 53.66; H, 4.43; N, 9.72. Found: C, 53.66; H, 4.56; N, 9.32.

EXAMPLE 96 Preparation of 1-[3-(4-Cyanobenzyl)-3H-imidazol-4-ylethyl]-4-(2methylbenzvl)piperidine-4-carbonitrile trifluoroacetate salt

ON

NC N N N HaC The title compound was prepared using the protocol described in Example 87, Step A D, substituting 3-methylbenzyl bromide with 2-methylbenzyl bromide in Step C, and in Example 78 substituting methyl 4-(3-methylbenzyl)piperidine-4-carboxylate hydiochloride salt with 4 2 -methylbenzyl)piperidine-4-carbonitrile hydrochloride salt. The crude product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase.

Anal. Calcd for C27H29N5-2.5 TFA-0.95 H20: C, 52.93; H, 4.52; N, 10.32. Found: C, 52.96; H, 4.64; N, 9.65.

EXAMPLE 97 WO 97/38665 PCTIUS97/06487 -215- Preparation of 4- 5-[ 4 -Hydroxymethyl-4-(4-methylpyridin-2-ylmethyl)piperidine-1 -ylmethyl]-2-methylimidazol- -vylmethyl benzonitrile

S/OH

NC N N C N

CH

3 Step A: Preparation of 2 -Hvdroxymethyl-4-methylpvridine A mixture of 2,4-dimethylpyridine N-oxide (10.9 g, 88.5 mmol) and trifluoroacetic anhydride (31 mL, 219 mmol) in dichloromethane (75 mL) was stirred at room temp. overnight. The product mixture was concentrated under vacuum. The residue was dissolved in a mixture of dichloromethane (75 mL) and aqueous sodium carbonate (225 mL, 2M), and stirred vigorously for 4 h. The resultant mixture was diluted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 1-2% methanol in chloroform gradient. Collection and concentration of appropriate fractions provided 2-hydroxymethyl-4-methylpyridine as clear oil.

Step B: Preparation of 2-Chloromethvl-4-methvlpvridine A mixture of 2-hydroxymethyl-4-methylpyridine (5.48 g, 44.5 mmol) and thionyl chloride (60 mL, 822 mmol) in benzene (150 mL) was stirred at room temp. overnight. The product mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to provide the title compound as oil. This alkylating reagent was passed through a small plug of activated basic alumina immediately before use.

Step C: Preparation of Ethyl N-tert-butoxycarbonyl-4-(4methylpyridin-2-ylmethyl)piperidine-4-carboxvlate WO 97/38665 PCT/US97/06487 -216- To a cold (-78 solution of ethyl N-tert-butoxycarbonylpiperidine-4-carboxylate (5.1 g, 19.8 mmol; Example 30, Step A) in anhydrous THF (50 mL), a solution of solution of sodium bis(trimethylsilyl)amide (20 mL, 1M, 20 mmol) was added over a period of 15 min.

The resultant mixture was stirred at -78 °C for 1 and 2chloromethyl-4-methylpyridine (3.5 g, 24.7 mmol) was added. The reacting mixture was allowed to warm to room temp. and stirred overnight. The product mixture was diluted with dichloromethane was washed with brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with ethyl acetate in hexane gradient. Collection and concentration of appropriate fractions provided the title compound.

Step D: Preparation of N-tert-Butoxycarbonyl-4-(4-methylpyridin- 2 -ylmethyl)-4-hydroxvmethylpiperidine To a slurry of lithium aluminum hydride (280 mg, 7.37 mmol) in anhydrous diethyl ether (30 mL) at 0 a solution of ethyl N-tert-butoxycarbonyl-4-( 4 -methylpyridin-2-ylmethyl)piperidine-4carboxylate (2.7 g, 7.45 mmol) in diethyl ether (20 mL) was added dropwise with the temperature of the reacting mixture maintained below The resulting mixture was stirred at 0 °C for 30 min, and quenched with successive addition of water (0.28 mL), 15% aqueous NaOH (0.28 mL), and water (0.84 mL). The resultant slurry was stirred at room temp. for 30 min., and filtered through a small plug of Celite. The filtrate was washed brine, dried over anhydrous magnesium sulfate, and filtered. Concentration of the filtrate under vacuum provided the title alcohol.

Step E: Preparation of 4-( 4 -methylpyridin- 2 -ylmethyl)-4-hydroxymethylpiperidine hydrochloride salt A solution of N-tert-butoxycarbonyl- 4 -(4-methylpyridin-2ylmethyl)-4-hydroxymethylpiperidine (1.8 g) in dichloromethane (100 mL) at 0 °C was saturated with hydrogen chloride gas. The resultant WO 97/38665 PCT/US97/06487 -217solution was sealed with a rubber septum and stirred at room temp. for h. The product solution was concentrated under vacuum to provide the title compound.

StepF: Preparation of 4 -Hydroxymethyl-4-(4-methylpyridin- 2-ylmethyl)piperidine- 1 -ylmethyl]-2-methylimidazol- 1ylmethvl benzonitrile A mixture of 4 4 -methylpyridin-2-ylmethyl)-4-hydroxymethylpiperidine hydrochloride salt (0.39 g, 1.3 mmol), 1-(4-cyanobenzyl)-2-methylimidazole-5-carboxyaldehyde (0.33 g, 1.5 mol; Example 31, Step diisopropylethylamine (0.57 mL, 3.25 mmol), anhydrous magnesium sulfate (0.55 activated molecular sieves 3 A powder (0.55 and anhydrous methanol (3.5 mL) was stirred at room temp. overnight. The pH of the mixture was adjusted to -5 with addition of glacial acetic acid. To the this mixture, a solution of sodium cyanoborohydride in THF (1.35 mL, 1 M, 1.35 mmol) was added slowly over a period of 8 h with a syringe pump, and stirred at room temp. overnight. The product mixture was diluted with chloroform, filtered through Celite. The filtrate was washed with aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 5% methanol in chloroform.

Collection and concentration of appropriate fractions provided a gum, which was triturated with anhydrous diethyl ether to provide the title compound as white solid.

Anal. Calcd for C26H31N50: C, 72.70; H, 7.27; N, 16.30. Found: C, 72.52; H, 7.08; N, 16.18.

EXAMPLE 98 Preparation of 4- 4 -Hydroxymethyl-4-(6-methylpyridin-2-ylmethyl)piperidine-1 -ylmethyl]-2-methylimidazol-1 -vlmethyl benzonitrile WO 97/38665 PCT/US97/06487 -218-

OH

NC N N N

CH

3 The title compound was prepared using the protocol described in Example 97, Step B F substituting 2-hydroxymethyl-4methylpyridine with 6 -methyl-2-pyridinemethanol in Step B.

Anal. Calcd for C26H31N50: C, 72.70; H, 7.27; N, 16.30. Found: C, 72.96; H, 7.34; N, 16.25.

EXAMPLE 99 Preparation of 4- {5-[4-Hydroxymethyl-4-( 2 -methylpyridin-4-ylmethyl)piperidine-1 -ylmethyl]-2-methylimidazol-1-vlmethyl }benzonitrile

OH

NC -C N o N

CH

3 Step A: Preparation of 2-Chloro-4-chloromethvl-6-methvlpyridine To a slurry of lithium aluminum hydride (0.45 g, 11.9 mmol) in anhydrous diethyl ether (40 mL) at 0 a solution of 2chloro-6-methylpyridine-4-carboxylic acid (2.0 g, 11.7 mmol) in diethyl ether (30 mL) was added. The resulting mixture was stirred at room temp. overnight, and quenched with successive addition of water (0.45 mL), 15% aqueous NaOH (0.45 mL), and water (1.35 mL). The resultant slurry was stirred at room temp. for 30 min., and filtered through a small plug of Celite. The filtrate was washed brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide 2 -chloro-4-hydroxymethyl-6-methylpyridine.

WO 97/38665 PCT/US97/06487 -219- The title compound was prepared using the protocol described in Example 97, Step B substituting 2-hydroxymethyl-4methylpyridine with 2 -chloro- 4 -hydroxymethyl-6-methylpyridine.

Step B: Preparation of Ethyl N-tert-butoxycarbonyl-4-(2-chloro-6methvlpyridin-4-vlmethyl)piperidine-4-carboxvlate The title compound was prepared using the protocol described in Example 97, Step C substituting 2-chloromethyl-4methylpyridine with 2 -chloro- 4 -chloromethyl-6-methylpyridine Step C: Preparation of Ethyl N-tert-butoxycarbonyl-4-(2-methylpyridin- 4 -vlmethvl)piperidine-4-carboxvlate A mixture of ethyl N-tert-butoxycarbonyl-4-(2-chloro-6methylpyridin-4-ylmethyl)piperidine-4-carboxylate (0.32 g, 0.81 mmol) and 5% palladium on charcoal (60 mg) in methanol (10 mL) was stirred under a balloon of hydrogen gas at room temp. for 3 h. The resultant mixture was filtered through a plug of Celite. The filtrate was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 3 5% methanol in chloroform gradient. Collection and concentration of appropriate fractions provided the title compound.

Step D: Preparation of 4- 4 -Hydroxymethyl-4-(2-methylpyridin- 4-ylmethyl)-piperidine- 1 -ylmethyl]-2-methylimidazol- ylmethyl }benzonitrile The title compound was prepared using the protocol described in Example 97, Step D F substituting ethyl N-tertbutoxycarbonyl-4-( 4 -methylpyridin-2-ylmethyl)piperidine-4carboxylate with ethyl N-tert-butoxycarbonyl-4-(2-methylpyridin-4ylmethyl)piperidine-4-carboxylate in Step D. The final product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.

WO 97/38665 PCTIUS97/06487 -220- Anal. Calcd for C26H31N50*3.35 TFA: C, 48.39; H, 4.27; N, 8.63.

Found: C, 48.42; H, 4.07; N, 8.49.

EXAMPLE 100 Preparation of 4- 4 -Hydroxymethyl-4-(4-chloropyridin-2-ylmethyl)piperidine- -vlmethvll-2-methylimidazol- 1-vlmethyl }benzonitrile

OH

NC N N- Step A: Preparation of 2 -Chloromethyl-4-chloropyridine To a slurry of lithium aluminum hydride (0.45 g, 11.9 mmol) in anhydrous diethyl ether (40 mL) at 0 a solution of methyl 4-chloro-pyridine-2-carboxylate (2.0 g, 11.7 mmol) in diethyl ether mL) was added. The resulting mixture was stirred at room temp.

overnight, and quenched with successive addition of water (0.45 mL), 15% aqueous NaOH (0.45 mL), and water (1.35 mL). The resultant slurry was stirred at room temp. for 30 min., and filtered through a small plug of Celite. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide 4 -chloro-2-hydroxymethylpyridine.

The title compound was prepared using the protocol described in Example 97, Step B substituting 2-hydroxymethyl-4methylpyridine with 4 -chloro-2-hydroxymethylpyridine.

Step B: Preparation of 4- 5-[ 4 -Hydroxymethyl-4-(4-chloropyridin- 2-ylmethyl)-piperidine-1 -ylmethyl]-2-methylimidazol- 1ylmethvl benzonitrile The title compound was prepared using the protocol described in Example 97, Step C F substituting 2 -chloromethyl-4methylpyridine with 2 -chloromethyl-4-chloropyridine in Step C.

WO 97/38665 PCT/US97/06487 -221 Anal. Calcd for C25H28N50C1: C, 66.73; H, 6.27; N, 15.56. Found: C, 66.52; H, 6.19; N, 15.35.

EXAMPLE 101 Preparation of 4- 4 -Methoxymethyl-4-(6-methylpyridin-2-ylmethyl)piperidine-1-vlmethyllimidazol- 1-vlmethyl }benzonitrile

SOCH

3 NC

N

CH

3 Step A: Preparation of N-tert-Butoxycarbonyl-4-(6-methylpyridin- 2 -vlmethyl)-4-methoxvmethvlpiperidine To a suspension of potassium hydride (52 mg, dry weight, 1.3 mmol; obtained from washing 0.15 g of 35% potassium hydride dispersion in mineral oil with hexanes and drying under a stream of argon) in anhydrous THF (10 mL), N-tert-butoxycarbonyl-4-(6methylpyridin-2-ylmethyl)-4-hydroxymethylpiperidine (0.3 g, 0.9 mmol; Example 98) in THF (2 mL) was added. The resultant mixture was stirred at room temp. for 1 h, and treated with methyl iodide pL, 0.96 mmol). The reacting mixture was stirred at room temp.

overnight. The product mixture was cooled to 0 quenched with water, and diluted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 20-30% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.

Step B: Preparation of 4-{5-[4-Methoxymethyl-4-(6-methylpyridin- 2-ylmethyl)-piperidine- 1 -ylmethyl]imidazol-1 -vlmethyl benzonitrile WO 97/38665 PCT/US97/06487 -222- The title compound was prepared using the protocol described in Example 97, Step E F substituting N-tert-butoxycarbonyl- 4 4 -methylpyridin- 2 -ylmethyl)-4-hydroxymethylpiperidine with Ntert-butoxycarbonyl- 4 -(6-methylpyridin-2-ylmethyl)-4-methoxymethylpiperidine in Step E. The final product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase.

Anal. Calcd for C26H31N50*3.35 TFA: C, 48.39; H, 4.27; N, 8.63.

Found: C, 48.42; H, 4.07; N, 8.49.

EXAMPLE 102 Preparation of 4- 5-[4-Hydroxymethyl-4-(6-hydroxypyridin-2ylmethyl)-piperidine- -ylmethyl]-2-methylimidazol-1ylmethyl benzonitrile

OH

N

OH

Step A: Preparation of 2 -Benzyloxy-6-methylpvridine N-oxide To a cold (0 solution of 2 -chloro-6-methylpyridine (24.6g, 193 mmol) in dichloromethane (100 mL), a solution of mchloro-per-benzoic acid (46.2 g, 268 mmol; purified) in dichloromethane (480 mL) was added over a period of 30 min. The reaction mixture was stirred at room temp. overnight, and concentrated to about 100 mL. The slurry was filtered, and the solid washed with ice-cold dichloromethane. The combined filtrate was washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under vacuum to provide 2 -chloro-6-methylpyridine N-oxide as clear colorless oil.

WO 97/38665 PCT/US97/06487 -223- To a slurry of sodium hydride (4.2 g, 105 mmol; dispersion in mineral oil) in anhydrous dimethyl sulfoxide (70 mL), benzyl alcohol (8.7 mL, 84 mmol) was added over a period of minute. The mixture was stirred at room temp. for 10 and treated with a solution of 2 -chloro-6-methylpyridine N-oxide (10 g, 70 mmol) in dimethyl sulfoxide (10 mL). The resultant mixture was stirred at room temp. overnight, quenched with water and aqueous hydrochloric acid (to pH The mixture was extracted with chloroform. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 1-4% methanol in chloroform gradient. Collection and concentration of appropriate fractions provided 2 -benzyloxy-6-methylpyridine N-oxide as pale brown oil.

Step B: Preparation of 2-Benzvloxv-6-chloromethvlpvridine A mixture of 2 -benzyloxy-6-methylpyridine N-oxide (3.4 g, 15.9 mmol) and acetic anhydride (125 mL) was heated under reflux for 1 h. The resulting solution was concentrated under vacuum, and the residue was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 10-20% ethyl acetate in hexane gradient. Collection and concentration of appropriate fractions provided 2 -acetoxymethyl-6benzyloxypyridine as colorless oil.

A mixture of 2 -acetoxymethyl-6-benzyloxypyridine (1.65 g, 6.4 mmol) and aqueous sodium hydroxide (0.58 mL, 40%) in methanol (10 mL) was stirred at room temp. overnight. The resulting solution was concentrated under vacuum, and the residue was partitioned between water and dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 0-5% ethyl acetate in WO 97/38665 PCT/US97/06487 -224chloroform gradient. Collection and concentration of appropriate fractions provided 2 -benzyloxy-6-hydroxymethylpyridine as colorless oil.

A mixture of 2 -benzyloxy-6-hydroxymethylpyridine (1.5 g, mmol) and thionyl chloride (10 mL, 137 mmol) in benzene (25 mL) was stirred at room temp. overnight. The product mixture was concentrated under vacuum. The residue was partitioned between chloroform and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 5% methanol in chloroform.

Collection and concentration of appropriate fractions provided 2benzyloxy-6-chloromethylpyridine as clear, colorless oil. This alkylating reagent was passed through a small plug of activated basic alumina immediately before use.

Step C: Preparation of N-tert-Butoxycarbonyl-4-(6benzyloxypyridin-2-vlmethyl)-4-hydroxvmethylpiperidine The title compound was prepared using the protocol described in Example 97, Step C D substituting 2-chloromethyl-4methylpyridine with 2 -benzyloxy-6-chloromethylpyridine in Step C.

Step D: Preparation of N-tert-Butoxycarbonyl-4-(6hvdroxvpvridin-2-vlmethvl)- 4 -hvdroxvmethylpiperidine A mixture of N-tert-butoxycarbonyl-4-(6benzyloxypyridin-2-ylmethyl)-4-hydroxymethylpiperidine (0.19 g, mmol) and 5% palladium on charcoal (38 mg) in absolute ethanol mL) was stirred under a balloon of hydrogen gas at room temp. for 3 h.

The resultant mixture was filtered through a plug of Celite. The filtrate was concentrated under vacuum to provide the title compound as colorless gum.

WO 97/38665 WO 9738665PCT/US97/06487 225 Step E: Preparation of 4-1{5-[4-Hydroxymethyl-4-(6hydroxypyridin-2-ylmethyl)piperidine- 1 -ylmethyl]-2methylimidazol- 1 -vimethyl I benzonitrile The title compound was prepared using the protocol described in Example 97, Step E F substituting N-tert-butoxycarbonyl.

4-(4-methylpyridin- 2 -ylmethyl)-4-hydroxymethylpiperidine with Ntert-butoxycarbonyl-4- (6-hydroxypyridin-2-ylmethyl)-4hydroxymethyl-piperidine in Step E.

Anal. Calcd for C25H29N502-1.25 H20-0.40 Et2O: C, 66.04; H, 7.40; N, 14.48. Found: C, 66.06; H, 7.02; N, 14.18.

EXAMPLE 102A Preparation of 4- 4 -Hydroxymethyl-4-quinolin-2-ylmethyl.

p2iperidine- 1 -ylmethyl)-2-methylimidazol- 1 -ylmethyllbenzonitrile NC N H3C NN The title compound was prepared using the protocol described in Example 97, Step C F substituting 2-hydroxyrnethyl-4methylpyridine with 2-chloromethylquinoline in Step C. The alkylating reagent, 2-chloromethylquinoline, was generated from 2chloromethylquinoline hydrochloride salt immediately before use.

Anal. Calcd for C29H31IN50: C, 74.8 1; H, 6.7 1; N, 15.04. Found: C, 74.45; H, 6.67; N, 15.07.

EXAMPLE 103 Preparation of Methyl 1- (4-cyanobenzyl)-3H-imidazol-4- ylmethyl] -4- (3-methylbenzoyl)piperidine-4-carboxylate WO 97/38665 PCT/US97/06487 -226- SC0 2

CH

3 NCN N N

CH

3 Step A: Preparation of Methyl N-tert-butoxycarbonyl-4-(3methylbenzovl)piperidine-4-carboxvlate To a cold (-78 solution of methyl N-tertbutoxycarbonyl-piperidine-4-carboxylate (0.25 g, 1.03 mmol; Example 3, Step B) in anhydrous THF (10 mL), a solution of sodium bis(trimethylsilyl)amide (1.2 mL, 1M, 1.2 mmol) was added over a period of 5 min. The resultant mixture was stirred at -78 oC for 1 h., and 3-methylbenzoyl chloride (135 gL, 1.02 mmol) was added. The reacting mixture was allowed to warm up to room temp. and stirred overnight. The product mixture was diluted with ethyl acetate and washed with brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 8- 10% ethyl acetate in hexane gradient. Collection and concentration of appropriate fractions provided the title compound.

Step B: Preparation of Methyl 4-(3-methylbenzoyl)piperidine-4carboxylate hydrochloride salt A solution of methyl N-tert-butoxycarbonyl-4-(3-methylbenzoyl)piperidine-4-carboxylate (77 mg) in ethyl acetate (10 mL) at 0 °C was saturated with hydrogen chloride gas. The resultant solution was stirred at 0 °C for 2.5 h. The product solution was concentrated under vacuum to provide the title compound.

Step C. Preparation of Methyl 1-[3-(4-cyanobenzyl)-3H-imidazol-4ylmethyll-4- 3 -methylbenzoyl)piperidine-4-carboxylate A solution of methyl 4-(3-methylbenzoyl)piperidine-4carboxylate hydrochloride salt (58 mg, 0.2 mmol), 1-(4-cyanobenzyl)- 5-chloromethylimidazole hydrochloride salt (52 mg, 0.19 mmol), and WO 97/38665 PCT/US97/06487 227 diisopropylethylamine (174 VpL, 1 mmol) in anhydrous acetonitrile (4 mL) was heated at 60 "C overnight. The resultant mixture was concentrated under vacuum, and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 2.5% methanol in ethyl acetate. Collection and concentration of appropriate fractions provided the title compound.

Anal. Calcd for C27H28N403-0.25 H20: C, 70.34; H, 6.23; N, 12.15.

Found: C, 70.27; H, 6.18; N, 12.27.

EXAMPLE 104 Preparation of 1-[3-(4-Cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-(3methylbenzovl)piperidine

H

NC

N

N CH 3 Step A: Preparation of 1-tert-Butoxycarbonyl-4-(3-methylbenzovl)piperidine A mixture of 1-tert-butoxycarbonylisonipecotic acid (5 g, 21.8 mmol; Example 81, Step N,O-dimethylhydroxylamine hydrochloride (2.12 g, 21.7 mmol), N-ethyl-N'-(3dimethylaminopropyl)carbodiimideohydrochloride (4.6 g, 24 mmol), 1hydroxy-7-azabenzotriazole (0.3 g, 2.2 mmol), and anhydrous dimethylformamide (50 mL) was stirred at room temp. overnight. The resulting mixture was concentrated under vacuum, and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide N-Methoxy-N-methyl 1-tert-butoxycarbonylisonipecotamide.

WO 97/38665 PCT/US97/06487 -228- To a cold (-78 solution of N-Methoxy-N-methyl 1-tertbutoxycarbonylisonipecotamide (1.54 g, 5.65 mmol) in anhydrous

THF

mL), a solution of 3 -methylphenylmagnesium bromide (25 mL, 1 M) in THF was added. The reacting mixture was allowed to warm up to room temp. and stirred overnight. The product mixture was quenched with 10% aqueous citric acid and diluted with diethyl ether. The organic extract was washed with aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 10-15% ethyl acetate in hexane gradient.

Step B: Preparation of 1-[ 3 4 -Cyanobenzyl)-3H-imidazol-4ylmethyll-4- 3 -methylbenzovl)pieridine The title compound was prepared as white solid according to the procedure described in Example 103, Step B C substituting methyl N-tert-butoxycarbonyl-4-(3-methylbenzoyl)piperidine-4carboxylate with N-tert-butoxycarbonyl-4-(3-methylbenzoyl)piperidine in Step B.

Anal. Calcd for C25H26N40: C, 75.35; H, 6.58; N, 14.06. Found: C, 75.38; H, 6.80; N, 14.12.

EXAMPLE 105 Preparation of 1-[ 3 4 -Cyanobenzyl)-3H-imidazol-4-ylmethyl]-4- (hvdroxv-m-tolvlmethvl)piperidine NC /N\

CH

3 WO 97/38665 PCT/US97/06487 -229- A solution of 1-[ 3 4 -cyanobenzyl)-3H-imidazol-4ylmethyl]-4-(3-methylbenzoyl)piperidine (175 mg, 0.44 mmol; Example 104) in methanol (5 mL) was treated with sodium borohydride (12 mg, 0.31 mmol) at room temp. The resultant solution was stirred at room temp. for 30 min., and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provided the title product.

Anal. Calcd for C25H28N40-0.25 Et20O0.55 H20: C, 72.80; H, 7.43; N, 13.06. Found: C, 72.74; H, 7.06; N, 13.05.

EXAMPLE 106 Preparation of 4- 4 -Hydroxymethyl-4-(3-tolylsulfanyl)piperidine 1vlmethyllimidazol-1-vlmethyl }benzonitrile trifluoroacetate salt

OH

NC

N

S

N

CH

3 Step A: Preparation of Ethyl N-tert-butoxycarbonyl-4-(3tolvlsulfanvl)piperidine-4-carboxvlate To a cold (-78 solution of ethyl N-tert-butoxycarbonylpiperidine-4-carboxylate (2.6 g, 10 mmol; Example 30, Step A) in anhydrous THF (40 mL), a solution of sodium bis(trimethylsilyl)amide (12 mL, 1M, 12 mmol) was added over a period of 10 min. The resultant mixture was stirred at -78 °C for 1 and di-3-methylphenyl disulfide (2.96 g, 12 mmol) was added. The reacting mixture was allowed to warm up to room temp. and stirred overnight. The product mixture was diluted with ethyl acetate and washed with brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 10-15% ethyl acetate in WO 97/38665 PCT/US97/06487 -230hexane gradient. Collection and concentration of appropriate fractions provided the title compound.

Step B: Preparation of N-tert-Butoxycarbonyl-4-hydroxymethyl-4- (3-tolylsulfanvl)piperidine To a slurry of lithium aluminum hydride (0.25 g, 6.6 mmol) in anhydrous diethyl ether (60 mL) at 0 a solution of ethyl N-tert-butoxycarbonyl- 4 -(3-tolylsulfanyl)piperidine-4-carboxylate (2.25 g, 5.9 mmol) in diethyl ether (5 mL) was added dropwise with the temperature of the reacting mixture maintained below 10 The resulting mixture was stirred at 0 °C for 1 and quenched with successive addition of water (0.25 mL), 15% aqueous NaOH (0.25 mL), and water (10.75 mL). The resultant slurry was stirred at room temp.

for one and filtered through a small plug of Celite. The filtrate was washed brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title alcohol.

Step C: Preparation of 4-hydroxymethyl-4-(3tolylsulfanvl)piperidine hydrochloride salt A solution of N-tert-butoxycarbonyl-4-hydroxymethyl-4- (3-tolylsulfanyl)piperidine (0.27 g) in dichloromethane (25 mL) at 0 °C was saturated with hydrogen chloride gas. The resultant solution was sealed with a rubber septum and stirred at 0 C for one h. The product solution was concentrated under vacuum to provide the title compound.

Step D: Preparation of 4- 4 -Hydroxymethyl-4-(3-tolylsulfanyl)piperidine-1 -ylmethyl]imidazol-1 -ylmethyl} benzonitrile trifluoroacetate salt A mixture of 4-hydroxymethyl-4-(3tolylsulfanyl)piperidine hydrochloride salt (0.23 g, 0.85 mmol), 1-(4- (0.20 g, 0.95 mmol; Example 1, Step diisopropyl-ethylamine (0.22 mL, 1.3 mmol), anhydrous magnesium sulfate (500 mg), activated powdered molecular sieves 3 A (500 mg), and anhydrous methanol (3 mL) was stirred at WO 97/38665 PCT/US97/06487 -231 room temp. overnight. The pH of the mixture was adjusted to -5 with addition of glacial acetic acid. To the this mixture, a solution of sodium cyanoborohydride in THF (0.9 mL, 1 M, 0.9 mmol) was added slowly over a period of 3 h. with a syringe pump, and stirred at room temp.

overnight. The product mixture was diluted with chloroform, filtered through Celite. The filtrate was washed with aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 3-5% methanol in chloroform gradient. Collection and concentration of appropriate fractions provided the free base. The product was purified with high pressure liquid column chromatography on C-18 reverse phase stationary phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.

Anal. Calcd for C25H28N40S-2.7 TFA-0.45 H20: C, 48.78; H, 4.26; N, 7.48. Found: C, 48.80; H, 4.28; N, 7.37.

EXAMPLE 107 Preparation of 5-[ 4 -Methoxymethyl-4-(3-tolylsulfanyl)piperidine-1vlmethyllimidazol-1-vlmethyl }benzonitrile trifluoroacetate salt

OCH

3 NC

N

I

N

CH

3 Step A: Preparation of N-tert-Butoxycarbonyl-4-methoxymethyl-4- (3-tolvlsulfanl)Dpiperidine To a suspension of potassium hydride (0.18 g, dry weight, mmol; obtained from washing 0.52 g of 35% potassium hydride dispersion in mineral oil with hexanes and drying under a stream of argon) in anhydrous THF (25 mL), N-tert-butoxycarbonyl-4-(3tolylsulfanyl)- 4 -hydroxymethylpiperidine (0.96 g, 2.8 mmol; Example 106, Step B) in THF (5 mL) was added. The resultant mixture was WO 97/38665 PCT/US97/06487 -232stirred at room temp. for 1 and treated with methyl iodide (0.31 mL, 4.97 mmol). The reacting mixture was stirred at room temp. overnight.

The product mixture was cooled to 0 quenched with water, and diluted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound.

Step B: Preparation of 4-Methoxymethyl-4-(3tolvlsulfanvl)Dpiperidine hydrochloride salt A solution of N-tert-butoxycarbonyl-4-methoxymethyl-4- (3-tolylsulfanyl)piperidine (0.18 g) in ethyl acetate (25 mL) at 0 °C was saturated with hydrogen chloride gas. The resultant solution was stirred at 0 °C for one h. The product solution was concentrated under vacuum to provide the title compound.

Step C: Preparation of 4- 4 -Methoxymethyl-4-(3-tolylsulfanyl)piperidine-1-ylmethyl]imidazol-1-ylmethyl }benzonitrile trifluoroacetate salt The title compound was prepared using the protocol described in Example 106, Step D substituting 4-hydroxymethyl-4-(3tolylsulfanyl)-piperidine hydrochloride salt with 4-methoxymethyl-4-(3tolylsulfanyl)-piperidine hydrochloride salt.

Anal. Calcd for C26H30N40S-2.45 TFA*1.1 H20: C, 49.77; H, 4.68; N, 7.51. Found: C, 49.77; H, 4.68; N, 7.39.

EXAMPLE 108 Preparation of 5-[4-Methoxymethyl-4-(3-tolylsulfinyl)piperidine-lylmethvllimidazol-1 -vlmethyl benzonitrile S- -OCH 3 NC N o WO 97/38665 PCT/US97/06487 -233- Step A: Preparation of N-tert-Butoxycarbonyl-4-methoxymethyl-4- (3-tolvlsulfinvyl)piperidine A mixture of N-tert-butoxycarbonyl-4-methoxymethyl-4- (3-tolylsulfanyl)piperidine (0.30 g, 0.85 mmol; Example 107, Step A) and sodium periodate (0.2 g, 0.94 mmol) in a mixture of methanol (6 mL) and water (4 mL) was stirred at room temp. overnight. The reaction mixture was diluted with dichloromethane. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 35% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.

Step B: Preparation of 4-{5-[4-Methoxymethyl-4-(3-tolylsulfinyl)piperidine-1-vylmethyllimidazol-1-vlmethvyl lbenzonitrile The title compound was prepared using the protocol described in Example 107, Step B substituting N-tert-butoxycarbonyl-4methoxy-methyl-4-(3-tolylsulfanyl)piperidine with N-tertbutoxycarbonyl-4-methoxymethyl-4-(3-tolylsulfinyl)piperidine, and in Example 103, Step C substituting 4 3 -methylbenzoyl)piperidine-4carboxylate hydrochloride salt with 4-methoxymethyl-4-(3tolylsulfinyl)piperidine hydrochloride salt.

Anal. Calcd for C26H30N402S*0.8 H20: C, 65.47; H, 6.68; N, 11.75.

Found: C, 65.53; H, 6.35; N, 11.66.

EXAMPLE 109 Preparation of 4- 5-[4-Methoxymethyl-4-(3-tolylsulfonyl)piperidine-1ylmethyllimidazol- I -vylmethvl benzonitrile NC OCH3

CH

3 WO 97138665 PCT/UjS97/06487 234 Step A: Preparation of N-tert-Butoxycarbonyl4methoxymethyj4- 3 -tolvlsulfinvl)piperidine A solution of N-tert-Butoxycarbonyl-4..methoxymethyj4- (3-tolylsulfanyl)piperidine (0.26 g, 0.73 mmol; Example 107, Step A) in acetonitrile (10 mL) was treated with a solution of Oxone (0.99 g, 1.6 mmol) in water (10 mL) and potassium bicarbonate (0.56 g, 5.6 mmol) in water (10 mL), and stirred at room temp. for 1 h. The reaction mixture was diluted with dichioromethane and water. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.

Step B: Preparation of 4-1{ 4 -Methoxymethyl-4-(3-.tolylsulfonyl)> p~iperidine- I -ylmethyllimidazol. 1 -ylmethyl I benzonitrile The title compound was prepared using the protocol described in Example 107, Step B substituting N-tert-butoxycarbonylb4 methoxy-methyl-4- 3 -tolylsulfanyl)piperidine with N-tertbutoxycarbonyl-4-methoxymethyl4(3-tolylsulfonyl)piperidine, and in Example 103, Step C substituting 4 3 -methylbenzoyl)piperidine-4carboxylate hydrochloride salt with 4 -methoxyrnethyl-4-(3.

tolylsulfonyl)piperidine hydrochloride salt.

Anal. Calcd for C26H3oN40 3 S00.6 H20: C, 63.81; H, 6.43; N, 11.45.

Found: C, 63.86; H, 6.11; N, 11.32.

EXAMPLE 110 Preparation of 1- [3 -(4-Cyanobenzyl)- 3 H-imidazol-4-ylmethyl]I-4-(3 methylphenvlamino)isonipecotamide WO 97/38665 PCT/US97/06487 -235- CO MH2 NC

N

H

N

CH

3 Step A: Preparation of 1-Benzyl-4-cyano-4-(3methylphenvlamino)-piperidine To a solution of 1-benzyl-4-piperidone (18.9 g, 0.1 mol) and 3-methylaniline (10.7 g, 0.1 mol) in glacial acetic acid (100 mL), trimethylsilyl cyanide (6.7 mL, 0.1 mol; Journal of Organic Chemistry, page 4207, year 1990) was added dropwise with the temp. of the reaction maintained <40 "C with a ice-water bath. After the addition was complete, the reaction mixture was stirred at room temp. for min, and poured into a mixture of ice (140 g) and concentrated ammonium hydroxide (168 The resultant mixture was extracted with chloroform (3 times). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residual oil was triturated with diisopropyl ether (300 mL) and stirred at room temp. overnight. The white solid precipitated was filtered to provide the title compound.

Step B: Preparation of 1-Benzyl- 4 -(3-methylphenylamino)isonipecotamide A mixture of 1-benzyl-4-cyano-4-(3-methylphenylamino)piperidine (7.6 g) and 90% sulfuric acid (53 mL) was heated 70 "C until all the solid dissolved 1 The resultant mixture was stirred at the temp. for 30 min., and poured into a mixture of ice (80 g) and concentrated ammonium hydroxide (75 The solution was basified with ammonium hydroxide, and extracted with chloroform. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound.

WO 97/38665 PCT/US97/06487 -236- Step C: Preparation of 4 3 -methylphenylamino)isonipecotamide hydrochloride salt A mixture of 1-benzyl-4-(3-methylphenylamino)isonipecotamide (0.42 g, 1.3 mmol) and 10% palladium on charcoal (0.88 g) in a mixture of ethanol (40 mL) and ethanol saturated with anhydrous hydrochloride gas (10 mL) was shaken in a Parr hydrogenator at 60 psi for 48 h. The resultant mixture was filtered through a plug of Celite, and the filtrate concentrated to provide the title compound.

Step D: Preparation of 1-[3-(4-Cyanobenzyl)-3H-imidazol-4vlmethyll- 4 3 -methylphenvlaminoyisonipecotamide The title compound was prepared using the protocol described in Example 106, Step D substituting 4-hydroxymethyl-4-(3tolylsulfanyl)-piperidine hydrochloride salt with 4-(3methylphenylamino)-isonipecotamide hydrochloride salt.

Anal. Calcd for C25H28N60*0.15 Et20*0.65 H20: C, 68.12; H, 6.88; N, 18.62. Found: C, 68.14; H, 6.73; N, 18.65.

EXAMPLE 111 Preparation of Ethyl l-[ 3 4 -Cyanobenzyl)-3H-imidazol-4-ylmethyl]-4- 3 -methvlphenylamino)piperidine-4-carboxvlate NC~S~ NdX/-7 02Et NC /N NC3

H

N

CH

3 Step A: Preparation of Ethyl I-Benzyl- 4 -(3-methylphenylamino)piperidine-4-carboxvlate A solution of 1-benzyl-4-(3-methylphenylamino)isonipecotamide (4.5 g, 13.9 mmol) and potassium hydroxide 53.5 mmol) in ethylene glycol (35 mL) was heated under reflux. The resulting mixture was diluted with water and neutralized with acetic WO 97/38665 PCT/US97/06487 -237acid. The white solid precipitated was filtered, washed with chloroform to provide 1-benzyl- 4 3 -methylphenylamino)piperidine-4-carboxylic acid.

A mixture of 1-benzyl-4-(3-methylphenylamino)piperidine- 4-carboxylic acid (3.81 g, 11.7 mmol) and concentrated sulfuric acid (2 mL) in absolute ethanol (80 mL) was heated under reflux overnight.

The resultant solution was concentrated under vacuum, and the residue was treated with chloroform saturated with ammonia gas. The mixture was filtered, and the filtrate concentrated. The residue was passed through a small plug of silica gel eluting with chloroform saturated with ammonia gas. Collection and concentration of the eluent under vacuum provided the title compound.

Step B: Preparation of Ethyl 1-[3-(4-Cyanobenzyl)-3H-imidazol-4ylmethyl]-4-(3-methylphenylamino)piperidine-4carboxvlate The title compound was prepared using the protocol described in Example 110, Step C D substituting 1-benzyl-4-(3methylphenyl-amino)isonipecotamide with ethyl 1-benzyl-4-(3methylphenylamino)-piperidine-4-carboxylate.

Anal. Calcd for C27H31N502-0.3 Et20: C, 70.59; H, 7.14; N, 14.60.

Found: C, 70.57; H, 7.07; N, 14.56.

EXAMPLE 112 Preparation of 4 -Cyanobenzyl)-3H-imidazol-4-ylmethyl]-4hydroxymethyl-4-(3-methylphenvlamino)piperidine N

N

CH

3 Step A: Preparation of 1-Benzyl-4-hydroxymethyl-4-(3methylphenylamino)piperidine WO 97/38665 PCT/US97/06487 -238- To a slurry of lithium aluminum hydride (330 mg, 8.7 mmol) in anhydrous diethyl ether (25 mL) at 0 a solution of ethyl 1benzyl-4-(3-methylphenylamino)piperidine-4-carboxylate (2.8 g, 7.94 mmol) in diethyl ether (10 mL) was added dropwise with the temp. of the reacting mixture maintained below 10 The resulting mixture was stirred at 0 °C for 30 min, and quenched with successive addition of water (0.33 mL), 15% aqueous NaOH (0.33 mL), and water (1 mL).

The resultant slurry was stirred at room temp. for 30 min., and was filtered through a small plug of Celite. The filtrate was washed brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title alcohol as white solid.

Step B: Preparation of 4 -hydroxymethyl-4-(3-methylphenylamino)piperidine hydrochloride salt A mixture of 1-benzyl-4-hydroxymethyl-4-(3methylphenylamino)piperidine (0.2 g, 0.64 mmol) and 10% palladium on charcoal (0.4 g) in a mixture of methanol (15 mL) and methanol saturated with anhydrous hydrochloride gas (10 mL) was shaken in a Parr hydrogenator at 60 psi for 24 h. The resultant mixture was filtered through a plug of Celite, and the filtrate was concentrated to provide the title compound.

Step C: Preparation of 1-[3-(4-Cyanobenzyl)-3H-imidazol-4ylmethyl]-4-hydroxymethyl-4-(3-methylphenylamino)piperidine The title compound was prepared using the protocol described in Example 110, Step D substituting 4-(3methylphenylamino)-isonipecotamide hydrochloride salt with 4hydroxymethyl-4-(3-methylphenylamino)piperidine hydrochloride salt.

Anal. Calcd for C25H29N50*0.1 H20: C, 71.94; H, 7.05; N, 16.78.

Found: C, 71.76; H, 7.09; N, 17.17.

EXAMPLE 112A WO 97/38665 PCT/US97/06487 -239- Preparation of 0- 1-[ 3 4 -Cyanobenzyl)-3H-imidazol-4-ylmethyl] methylphenvlamino)piperidvl-4-methyl I carbamate 0

NH

2 0 NC N

N.

N

CH

3 Step A: Preparation of 0-[1-Benzyl-4-(3methylphenvlamino)piperidvl-4-methyllcarbamate A mixture of 1-benzyl-4-hydroxymethyl-4-(3methylphenyl-amino)piperidine (0.25 g, 0.81 mmol; Example 112, Step 1,1'-carbonyldiimidazole (0.14 g, 0.89 mmol) and dichloromethane (2 mL) was stirred at room temp. overnight. The resultant solution was concentrated, and the residue subjected to column chromatography on silica gel eluting with 5% methanol in chloroform. Collection and concentration of appropriate fraction provided 1-[1-benzyl-4-(3methylphenylamino)-piperidylmethyloxy]carbonyl 1'-imidazole. This material was dissolved in chloroform saturated with ammonia gas. The reaction mixture was sealed with a rubber septum, and stirred at room temp. for 2 days. The resultant mixture was concentrated, and the residue subjected to column chromatography on silica gel eluting with 8% methanol in chloroform. Collection and concentration of appropriate fraction provided the title compound.

Step B: Preparation of O- 1-[3-(4-Cyanobenzyl)-3H-imidazol-4ylmethyl]-4-( 3 -methylphenylamino)piperidyl-4methyl I carbamate The title compound was prepared using the protocol described in Example 110, Step C D substituting 1-benzyl-4-(3methylphenyl-amino)isonipecotamide with 0-[1-Benzyl-4-(3methylphenylamino)-piperidyl-4-methyl]carbamate.

WO 97/38665 PCT/US97/06487 -240- Anal. Calcd for C26H30N602-0.2 H20: C, 67.56; H, 6.63; N, 18.18.

Found: C, 67.60; H, 6.28; N, 18.13.

EXAMPLE 112B Preparation of 1-[3-(4-Cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-(3methylphenvlamino)piperidvl-4-methylurea 0

NH

2

N

CH

3 Step A: Preparation of 1-Benzyl-4-(3-methylphenylamino)-4aminomethylpiperidine A mixture of 1-benzyl-4-cyano-4-( 3 -methylphenylamino)piperidine (4.0 g; Example 110, Step A) and 5% rhodium on alumina (4 g) in absolute ethanol (100 mL) treated with anhydrous ammonia gas (8 g) was hydrogenated at 55 psi at room temp. for 24 h. The resultant mixture was filtered through a plug of Celite, and the filtrate concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 1:1 mixture of 5% methanol in chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provided the title triamine as clear, colorless, viscous oil.

FAB MS m/e 310 (M+1) Step B: Preparation of [1-Benzyl-4-(3methylphenylamino)piperidin-4-ylmethyllurea A mixture of 1-benzyl-4-(3-methylphenylamino)-4aminomethylpiperidine (247 mg, 0.79 mmol) and nitrourea (253 mg, 2.4 mmol) in mixture of acetonitrile (1 mL) and water (10 drops) was stirred at room temp. for 48 hrs. The resultant mixture was concentrated under vacuum, and the residue was subjected to column WO 97/38665 PCT/US97/06487 -241 chromatography on silica gel eluting with a 1:1 mixture of methanol in chloroform and chloroform saturated with ammonia gas.

Step C: Preparation of 1-[3-(4-Cyanobenzyl)-3H-imidazol-4vImethyll-4- 3 -methvlphenvlamino)piperidvl 4 -mehvlurea The title compound was prepared using the protocol described in Example 110, Step C D substituting 1-benzyl-4-(3methylphenylamino)isonipecotamide with [1-benzyl-4-(3methylphenylamino)piperidin-4-ylmethyl] urea.

EXAMPLE 112C Preparation of l-[3-(4-Cyanobenzyl)-3H-imidazol-4-ylmethyl]-4(3methvlphenvlamino'piperidvl-4-methylsulfamide O0

S-NH

2

N

NC N H_ N

N

H

N

CH

3 Step A: Preparation of [1-Benzyl-4-(3methylphenylamino)piperidin-4-vlmethyllsulfamide To a cold (5 solution of chlorosulfonyl isocyanate in THF, anhydrous formic acid is added (Journal of Organic Chemistry, vol 54, page 5825, (1989)). The resultant mixture is stirred until gas evolution ceased, and treated with a solution of 1-benzyl-4-(3methylphenylamino)-4-aminomethylpiperidine in THF. The mixture is stirred at room temp. overnight to provide the title compound.

WO 97/38665 WO 9738665PCTIUS97/06487 242 Step B: Preparation of 1- [3 -(4-Cyanobenzyl)-3H-imidazol-4ylmethyl] -4-(3-methylphenylamino)piperidyl-4methyl sulfamide The title compound is prepared using the protocol described in Example 110, Step C D substituting I1-benzyl-4- (3 methylphenylamino)-isonipecotamide with [1 -benzyl-4-(3 methylphenylamino)piperidin-4-ylmethyl] sulfamide, EXAMPLE 113 Preparation of 4- [4-(Hydroxydiphenylmethyl)piperidin- 1ylmethyll imidazol- I -yimethyl I benzonitrile NC -N OH The title compound was prepared as white solid according to the procedure described in Example 103, Step C substituting methyl 4- (3-methylbenzoyl)piperidine-4-carboxylate hydrochloride salt with (x,cu-diphenyl-4-piperidinemethanol in Step B.

Anal. Calcd for C30H30N40: C, 77.59; H, 6.70; N, 11.83. Found: C, 77.39; H, 6.69; N, 12.00.

EXAMPLE 114 Preparation of 4- 4 -(Hydroxydiphenylmethyl)piperidine- 1carbonyil imidazol- 1 -ylmethyl I benzonitrile WO 97/38665 WO 9738665PCT/US97/06487 243 0 NC\ N4O

N

The title compound was prepared as white solid according to the procedure described in Example 39 substituting 4-(3methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with (X,cdiphenyl-4-piperidinemethanol in Step B.

Anal. Calcd for C30H28N40-0.8 H20-0.35 Et2O: C, 72.96; H, 6.45; N, 10.84. Found: C, 73.00; H, 6.36; N, 10.83.

EXAMPLE 115 Preparation of 2 4 -(Hydroxydiphenylmethyl)piperidin-1-yl]-2oxoethyl 3H-imidazol- 1 -ylmethyl)benzonitrile 0 NC N0 OH

N

The title compound was prepared as white solid according to the procedure described in Example 38, Step B substituting 4-(3methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with xI,udiphenyl-4-piperidinemethanol in Step B.

Anal. Calcd for C31IH30N402: C, 75.89; Hl, 6.16; N, 11.42. Found: C, 75.60; H, 6.20; N, 11.25.

EXAMPLE 116 1 -(Piperidin-4-ylmethyl)-5-(4-cyanobenzyl)imidazoLe bis hydrochloride WO 97/38665 PCT/US97/06487 -244- Step A: I-Tritvl-4-(4-cvanobenzvl)-imidazole To a suspension of activated zinc dust 3 .57g, 54.98 mmol) in THF (50 mL) was added dibromoethane (0.315 mL, 3.60 mmol) and the reaction stirred under argon for 45 minutes, at 20 0 C. The suspension was cooled to 0°C and a-bromo-p-tolunitrile (9.33g, 47.6 mmol) in THF (100 mL) was added dropwise over a period of 10 minutes. The reaction was then allowed to stir at 20 0 C for 6 hours and bis(triphenylphosphine) Nickel II chloride (2.40g, 3.64 mmol) and 4iodo-1-tritylimidazole (15.95g, 36.6 mmol, S. V. Ley, et al., J. Org.

Chem. 56, 5739 (1991)) were added in one portion.The resulting mixture was stirred 16 hours at 20 0 C and then quenched by addition of saturated NH 4 CI solution (100 mL) and the mixture stirred for 2 hours.

Saturated aq. NaHCO 3 solution was added to give a pH of 8 and the solution was extracted with EtOAc (2 x 250 mL), dried (MgSO 4 and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 0-20% EtOAc in CH 2 C12) to afford the title compound as a white solid.

1 H NMR (CDC13, 400Mz) 6 (7.54 (2H, d, J=7.9Hz), 7.38(1H, 7.36- 7.29 (11H, 7.15-7.09(6H, 6.58(1H, s) and 3.93(2H, s) ppm.

Step B: N-t-butoxvcarbonvl-4-hvdroxvmethyl piperidine.

To a solution of N-t-butoxycarbonyl isonipecotic acid (15.0 g, 65.4 mmol) from example 3 step A, in anhydrous THF (50ml), was added borane (65.4 ml of a 1M solution in THF, 65.4 mmol) at room temperature. After 72 hours methanol (50ml) was added and the solvent evaporated in vacuo. The residue was dissolved in methanol (100ml) and the solvent evaporated in vacuo. The eesidue was partitioned between EtOAc and NaHCO 3 the organic layer separated and washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography (Silica gel, eluting with 50% EtOAc in hexanes to afford the title compound.

Step C: Butoxycarbonyl-piperidin-4-ylmethyl)-5-(4cyanobenzvl)imidazole WO 97/38665 PCTfUS97/06487 -245- To 1-trityl- 4 -(4-Cyanobenzyl)-imidazole (1.99g, 4.64 mmol) in CH 2 Cl 2 (9.3 mL), Hunigs base (1.62mL, 9 2 8mmol) and the product from step B (1.0g 4.64mmol) at -78 0 C was added trifluoromethanesulfonic anhydride (0.78mL, 4.64 mmol). After 45minutes the reaction was allowed to warm to room temperature. The solvent was evaporated and the residue was dissolved in methanol ml) and heated at reflux for 1 hour, cooled and evaporated to dryness.

The residue was partitioned between sat. aq. NaHCO3 solution and CH2C1 2 The organic layer was dried, (MgS04) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 3% MeOH in CH 2 C1 2 to afford the title compound.

1 H NMR CD30D 6 7.69(2H, d, J=8.05Hz), 7.61(1H,s), 7.41(2H,d, J=8.05Hz), 6.75(1H,s), 4.10(2H,s), 4.03(2H,brd, J=13.4Hz), 3.73(2H,d, J=7.3Hz),3.50-3.30(2H,m), 2.60(2H,m), 1.80-1.55(2H,m), 1.43(9H,s) and 1.10-1.00 (2H,m) ppm.

Step D: 1-(Piperidin- 4 -ylmethyl)-5-(4-cyanobenzyl)imidazole bis hydrochloride Into a solution of the product from step C (0.843g, 2.21 mmol) in EtOAc (200 mL) at OoC was bubbled HCI gas. After minutes the solvent was evaporated in vacuo to afford the title compound as a foam.

Anal. Calcd for C17H20N4*2.15 HCI*0.55 H 2 0 C, 55.38; H, 6.36; N, 15.2. Found: C, 55.39; H, 6.36; N, 14.82.

EXAMPLE 117 1-(1 -Phenylpiperidin-4-ylmethyl)-5 -(4-cyanobenzyl)imidazole hydrochloride salt The amine from Example 116, step D (0.16g, 0.566 mmol) and triethylamine (0.158mL 1.32 mmol) in CH 2 C1 2 (2.5 mL) at room temperature was added triphenyl bismuth (0.409g, 8.49 mmol) and Copper (II) acetate (0.154g, 0.849 mmol) and the reaction was stirred WO 97/38665 PCT/US97/06487 -246for 12 hours. The reaction was quenched by the addition of sat and CH 2 Cl 2 The mixture was filtered and the filtrate extracted with

CH

2 C1 2 dried, (MgS04) and the solvent evaporated in vacuo. The residue was chromatographed (Silica Gel, eluting with 3% MeOH in

CH

2 C1 2 The product was converted to the hydrochloride salt.

1 H NMR CD 3 0D 6 9.11(1H,s), 7.78(2H,d, J=8.2Hz), 7.71(2H,d, J=7.9Hz), 7.70-7.50(5H,m), 7.28(1H,s), 4.33(2H,s), 4.21(2H,d, 3.80-3.50(4H,m), 2.38(1H,m) and 2 .05-1.85(4H,m) ppm.

Anal. Calcd for C23H24N4*2.15 HCl*1.40 HO 2 0 C, 60.05; H, 6.34; N, 12.18. Found: C, 60.07; H, 6.34; N, 12.35.

FAB HRMS exact mass calcd for C23H25N4: 357.2073724(MH+); found 3572079910.

EXAMPLE 118 1-(1-(2-methylphenyl)piperidin-4-ylmethyl)-5-(4cyanobenzvl)imidazole hydrochloride salt The amine from Example 116, step D (0.16g, 0.566 mmol) and triethylamine (0.158mL 1.32 mmol) in CH 2 1 2 (2.5 mL) at room temperature was added tris-2-methylphenyl bismuth (0.

4 40g, 8.49 mmol) and Copper (II) acetate (0.154g, 0.849 mmol) and the reaction was stirred for 12 hours. The reaction was quenched by the addition of sat NH40H and CH 2 C1 2 The mixture was filtered and the filtrate extracted with CH2Cl 2 dried, (MgSO 4 and the solvent evaporated in vacuo. The residue was chromatographed (Silica Gel, eluting with 3% MeOH in CH2Cl 2 The product was converted to the hydrochloride salt.

1 H NMR CD30D 6 9.11(1H,s), 7.78(2H,d, J=7.8Hz), 7.60 (1H,m), 7.55(2H,d, J=7.9Hz), 7.50-7.35(3H,m), 7.29(1H,s), 4.33(2H,s), 4.21(2H,d, J=7.1Hz), 3.80-3.40(4H,m), 2.57(3H,s), 2.31(1H,m) and 2.05-1.85(4H,m) ppm.

Anal. Calcd for C24H26N4*2.45 HCl*1.55 H 2 0 C, 59.10; H, 6.52; N, 11.49. Found: C, 59.16; H, 6.51; N, 11.26.

WO 97/38665 PCT/US97/06487 247 EXAMPLE 119 1-(1-(2-chlorobenzoyl)piperidin-4-ylmethyl)-5-(4cyanobenzyl)imidazole hydrochloride salt The amine hydrochloride from Example 116, step D (0.061g, 0.194 mmol) and triethylamine (0.108mL 0.775 mmol) in

CH

2 C1 2 (2.0 mL) at 0°C was added 2 chlorobenzoyl chloride (0.025mL, 0.203 mmol) and the reaction was allowed to warm to room temperature and stirred for 12 hours. The reaction was quenched by the addition of sat Na2CO3 and extracted into EtOAcThe organic extracts were washed with brine, dried, (MgSO 4 and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, eluting with 3% MeOH in CH 2 C1 2 The product was converted to the hydrochloride salt.

FAB MS 419 (MH+) Anal. Calcd for C24H22N40C1*1.35 HC1-0.35 CH 3 CN C, 61.58; H, 5.13; N, 12.84. Found: C, 61.48; H, 5.47; N, 12.84.

EXAMPLE 120 1-(1-(3-chlorobenzoyl)piperidin-4-ylmethyl)-5-(4cyanobenzyl)imidazole hydrochloride salt The amine hydrochloride from Example 116, step D (0.059g, 0.189 mmol) and triethylamine (0.105mL 0.775 mmol) in

CH

2 C1 2 (2.0 mL) at 0°C was added 3-chlorobenzoyl chloride (0.025mL, 0.198 mmol) and the reaction was allowed to warm to room temperature and stirred for 12 hours. The reaction was quenched by the addition of sat Na 2

CO

3 and extracted into EtOAcThe organic extracts were washed with brine, dried, (MgSO 4 and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, eluting with 3% MeOH in CH 2 C12). The product was converted to the hydrochloride salt.

FAB MS 419 (MH+) WO 97/38665 PCT/US97/06487 -248- Anal. Calcd for C24H22N40Cl*1.35 HC1l0.25 CH 3 CN C, 61.63; H, 5.09; N, 12.47. Found: C, 61.68; H, 5.42; N, 12.44.

EXAMPLE 121 1-(1-(3-chlorobenzenesulfonyl)piperidin-4-ylmethyl)-5-(4cvanobenzyl)imidazole hydrochloride salt The amine hydrochloride from Example 116, step D (0.066g, 0.187 mmol) and triethylamine (0.84mL 0.60 mmol) in

CH

2 C1 2 (2.0 mL) at 0°C was added 3-chlorobenzenesulfonyl chloride (0.043g, 0.21 mmol) and the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by the addition of sat Na 2

CO

3 and extracted into EtOAcThe organic extracts were washed with brine, dried, (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, eluting with 3% MeOH in CH 2 C1 2 The product was converted to the hydrochloride salt.

Anal. Calcd for C 23

H

23

N

4 02C1S*1.00 HCl*0.35 H 2 0 C, 55.50; H, 5.00; N, 11.26. Found: C, 55.51; H, 4.99; N, 11.31.

1 H NMR CD 3 0D 5 8.91(1H,s), 7.75-7.55(6H,m), 7.44(2H,d, J=8.6Hz), 7.27(1H,s), 4.21(2H,s), 4.02(2H,d, J=7.1Hz), 3.79 (2H,d, J=11.9Hz), 2.16(2H,dd, J=12.1 and 10.2Hz), 1.70-1.50(3H,m), and 1.40- 1.20(2H,m) ppm.

EXAMPLE 122 1-(1 -(3-chlorobenzyl)piperidin-4-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt To the amine hydrochloride from Example 116, step D (0.092g, 0.261 mmol) and 3A molecular sieves (0.30g) in MeOH mL) at room temperature was added 3-chlorobenzaldehyde (0.043g, 0.21 mmol) and the reaction was stirred for 30 minutes. sodium cyanoborohydride (24.5mg was added in one portion and the reaction WO 97/38665 PCT/US97/06487 249 stirred for a furthur 16 hours, The reaction was filtered and the filtrate evaporated in vacuo. The residue was partitio between CH 2 C1 2 and sat Na 2

CO

3 and extracted into CH 2 C1 2 The organic extracts were dried, (MgSO 4 and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, gradient elution with 2-5% MeOH in

CH

2 C12). The product was converted to the hydrochloride salt.

Anal. Calcd for C23H 23

N

4 0 2 C1S-2.50 HC1-0.65 H 2 0 C, 56.77; H, 5.72; N, 11.03. Found: C, 56.74; H, 5.71; N, 10.81.

1H NMR CD30D 5 9.04(1H,s), 7.75(2H,d, J=7.9Hz), 7.65(1H,s), 7.60-7.40(5H), 7.26(1H,s), 4.33(2H,s), 4.27(2H,s), 4.11(2H,d, J=7.1Hz), 3.50 (2H,d, J=8.1Hz), 3.00(2H,t, 11.9Hz), 2.17(1H,m), 1.90- 1.80(2H,m), 1.80-1.60(2H,m) ppm.

EXAMPLE 123 2-[3-(4-cyanobenzyl)-3H-imidazol-1-yl]-N-( -phenylpiperidin-4vl)acetamide hydrochloride StepA: 8-Phenvl- 1,4-dioxa-8-azaspiro[4.51decane Palladium (II) chloride (1.40 g, 7.9 mmol) and tri-otolylphosphine (4.80 g, 15.8 mmol) were stirred in dry toluene (60 mL) at room temperature under an argon atmosphere for 30 min. The solution was then diluted with dry toluene (800 mL) and to this was added 1,4-dioxa-8-azaspiro[4.5]decane (27.4 g, 191 mmol); sodium tertbutoxide (21.4 g, 223 mmol); and bromobenzene (25.0 g, 159 mmol).

The mixture was heated to 100 oC for 18 hrs then allowed to cool.

Ether (300 mL) was added and the mixture was washed with brine (800 mL). The brine was extracted with a further portion of ether (200 mL) and the combined organic extracts were dried over MgS04, filtered, and concentrated in vacuo to give a dark oil. The crude product was purified by flash column chromatography on silica, eluting with hexane 10% ethyl acetate to yield the product as a pale yellow oil.

'H NMR (CDC13) 6 7.25 (2H, dd, J=8,7Hz); 6.95 (2H, d, J=8Hz); 6.83 (1H, t, J=7Hz); 3.99 (4H, 3.32 (4H, 1.84 (4H, m).

WO 97/38665 PCTIUS97/06487 -250- Step B: 1-Phenvlpiperidin-4-one 8-Phenyl- 4 -dioxa-8-azaspiro[4.5]decane (18.1 g, 82.5 mmol) was dissolved in a mixture of acetic acid (150 mL), water (150 mL), and conc. hydrochloric acid (38 mL) and the resulting solution was heated to 50 °C for 18 hrs. The reaction mixture was cooled in an ice-water bath, and sodium hydroxide pellets were added in portions until the mixture was neutralized. This mixture was extracted with dichloromethane (3 x 300 mL) and the combined organic extracts were dried over MgSO 4 filtered, and concentrated in vacuo to give a dark oil. Chromatography on silica gel, eluting with hexane 10% ethyl acetate gave the product as a pale yellow oil.

'H NMR (CDCl 3 5 7.30 (2H, dd, J=9,7Hz); 6.99 (2H, dd, J=9,1Hz); 6.89 (1H, tt, J=7,1Hz); 3.61 (4H, t, J=6Hz); 2.56 (4H, t, J=6Hz).

Step C: 1-Phenylpiperidin-4-vlamine 1-Phenylpiperidin-4-one (3.0 g, 17.1 mmol) was dissolved in methanol (250 mL) and acetic acid (147 mL), and ammonium acetate (67 g, 870 mmol) was added portionwise. The mixture was stirred for 4 hrs at room temperature, then cooled to 0 oC (ice-water) and sodium cyanoborohydride (1.6 g, 25 mmol) was added, then the reaction mixture was stirred at room temperature for 18 hrs. Water (20 mL) was added, and the mixture was concentrated under reduced pressure.

The residue was adjusted to pH 12 with 15% aqueous NaOH and the resulting mixture was extracted with dichloromethane (3 x 100 mL).

The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with dichloromethane 3% methanol 0.3% NH 4 OH to give the product as a pale solid.

'H NMR (CDCl 3 7.26 (2H, 6.96 (2H, 6.83 (1H, 3.65 (2H, 2.87-2.75 (3H, 1.92 (2H, 1.50 (2H, 1.32 (2H, br s).

FAB MS: 177 WO 97/38665 WO 9738665PCTfUS97/06487 251 Step D: 2-[3-(4-Cyanobenzyl)-3H-imidazol. 1 1jphenvlpiperidin-4-yl~acetamide hydrochloride 1 -Phenylpiperidin-4-ylamine (40 mg, 0.227 mmol), lithium 4 -cyanobenzyl)-3H-imidazol-4-yl]acetate (56 mg, 0.227 mmol), 1hydroxybenzotriazole hydrate (46 mg, 0.34 mmol), dimethylaminopropyl)-3-ethylcarbodiimjde hydrochloride (87 mg, 0.45 mmol), and N,N-diisopropylethylamine (99 JIL, 0.57 mmol) were added to degassed DMF (2 mL) and the mixture was stirred for 18 hrs at room temperature then concentrated in vacuo. The residue was added to sat.

NaHCO3 (aq) (5 mL) and extracted with dichloromethane (3 x 3 mL).

The combined organic extracts were dried over MgS 04, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with dichioromethane methanol 0.05% NH 4 0H to give the product as a free base. This was lyophilized from HCI (aq) acetonitrile to give the title compound as a white solid.

Elemental analysis calculated for C 24

H

25

N

5 0* 1.2 HCl'0.5 H 2 0'0.

CH

2 Cl 2 C: 62.37; H: 5.96; N: 15.06 Found: C: 62.64; H: 6.35; N: 14.67 H NMR (CD 3 OD) 8 8.79 (lH, d, J=lHz); 7.79 d, J=8Hz); 7.47- 7.40 (3H, in); 7.23 dd, J=7,9Hz); 7.00 d, 1=8Hz); 6.86 (1H, t, 1=7Hz); 5.55 (2H, 3.70-3.57 (3H, in); 3.60 2.83 (2H, td, J=12,2H-z); 1.92 (2H, dd, J=14,4Hz); 1.59 (2H, qd, 1=12,4Hz).

FAB MS: 400 EXAMPLE 124 2- [3-(4-cyanobenzyl)-3H-imidazol- 1-yl] -N-benzyl-N- (1p2henvlpiperidin-4-yl) acetamide hydrochloride Step A- B enzyl(l1-phenylpiperidin-4-yl)amine 1 -Phenylpiperidin-4-one (2.0 g, 11.4 mmol) (from Example 123) and benzylamine (1.33 g, 12.5 mmol) were dissolved in WO 97/38665 PCT/US97/06487 -252- 1,2-dichloroethane (35 mL) and acetic acid (1.36 g, 22.6 mmol) was added. The mixture was stirred for 2 hrs at room temperature, then cooled to 0 °C (ice-water) and sodium triacetoxyborohydride (3.14 g, 14.8 mmol) was added, then the reaction mixture was stirred at room temperature for 18 hrs. Sat. NaHCO 3 (aq) (30 mL) was added, and the organic layer was extracted. The aqueous phase was extracted with dichloromethane (2 x 50 mL). The combined organic extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexane 30% ethyl acetate to give the product as a white solid.

'H NMR (CDC1 3 8 7.35-7.21 (7H, 6.94 (2H, dd, J=9,1Hz); 6.82 (1H, tt, J=7,1Hz); 3.86 (2H, 3.66 (2H, dt, J=13,3Hz); 2.78 (2H, td, J=12,2Hz); 2.68 (1H, tt, J=10,4Hz); 2.01 (2H, 1.55 (2H, qd, J=12,4Hz); 1.35 (1H, br s).

Step B: 2-[3-(4-cyanobenzyl)-3H-imidazol-1 -yl]-N-benzyl-N-( 1 phenylpiperidin-4-vl)acetamide hydrochloride Benzyl(l-phenylpiperidin-4-yl)amine (50 mg, 0.188 mmol), lithium [3-(4-cyanobenzyl)-3H-imidazol-4-yl]acetate (51 mg, 0.206 mmol), 1-hydroxybenzotriazole hydrate (38 mg, 0.28 mmol), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.38 mmol), and N,N-diisopropylethylamine (82 gL, 0.47 mmol) were added to degassed DMF (2 mL) and the mixture was stirred for 18 hrs at room temperature then concentrated in vacuo. The residue was added to sat. NaHCO 3 (aq) (5 mL) and extracted with dichloromethane (3 x 3 mL). The combined organic extracts were dried over MgSO 4 filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane 4% methanol 0.01% NH40H to give the product as a free base. This was lyophilized from HCI (aq) acetonitrile to give the title compound as a white solid.

Elemental analysis calculated for C 31

H

31

N

5 0*1.2 HC1-0.35 H20*0.15

CH

2 C1 2 WO 97/38665 PCT/US97/06487 -253- C: 67.72; H: 6.06; N: 12.68 Found: C: 67.87; H: 6.39; N: 12.28 'H NMR (CD30D) 8.88-8.86 (1H, 7.81-7.69 (2H, 7.55-7.19 7.00-6.97 (2H, 6.86 (1H, t, J=7Hz); 5.51-5.46 (2H, m); 4.63-4.59 (2H, 4.52-3.67 (5H, 2.86-2.76 (2H, 1.95-1.73 (4H, m).

FAB MS: 490 EXAMPLE 125 2-[3-(4-Cyanobenzyl)-3H-imidazol-1-yl]-N-( 1 -phenylpiperidin-4-yl)- N-pyridin-4-vlmethylacetamide hydrochloride The title compound was prepared according to the procedure in Example 124, Steps A B, with 4-(aminomethyl)pyridine replacing benzylamine in Step A. The product was treated with HCI in ethyl acetate ethanol to give the hydrochloride salt.

Elemental analysis calculated for C 30

H

30

N

6 0*3 HCl-0.5 EtOH-0.5 CH2C12: C: 56.85; H: 5.60; N: 12.63 Found: C: 57.00; H: 5.92; N: 12.80 FAB MS: 491 (MH EXAMPLE 126 2-[3-(4-cyanobenzyl)-3H-imidazol-1-yl]-N-phenethyl-N-(1phenylpiperidin-4-yl)acetamide hydrochloride The title compound was prepared according to the procedure in Example 124, Steps A B, with phenethylamine replacing benzylamine in Step A. The product was treated with HCI in ethyl acetate to give the hydrochloride salt.

Elemental analysis calculated for C 32

H

33

N

5 0*2 HCl*0.2 H 2 0: C: 66.24; H: 6.15; N: 12.07 Found: C: 66.24; H: 5.91; N: 11.84 WO 97/38665 PCT/US97/06487 -254- FAB MS: 504 (MH EXAMPLE 127 4- -Phenylpiperidin-4-ylamino)methyl] imidazol-1 ylmethyl }benzonitrile hydrochloride Step A: 4- -Phenylpiperidin-4-ylamino)methyl]imidazol-1ylmethvl benzonitrile hydrochloride l-Phenylpiperidin-4-ylamine (75 mg, 0.43 mmol) (from Example 123) and 4-(5-formylimidazol-1-ylmethyl)benzonitrile (99 mg, 0.47 mmol) were dissolved in 1,2-dichloroethane (2 mL) and acetic acid (49 gL, 0.86 mmol) was added. The mixture was stirred for 2 hrs at room temperature, then sodium triacetoxyborohydride (117 mg, 0.55 mmol) was added, then the reaction mixture was stirred at room temperature for 18 hrs. Sat. NaHCO 3 (aq) (30 mL) was added, and the organic layer was extracted. The aqueous phase was extracted with dichloromethane (2 x 5 mL). The combined organic extracts were dried over MgSO 4 filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with dichloromethane methanol 0.5% NH 4 OH to give the product as a free base. This was lyophilized from HCI (aq) acetonitrile to give the title compound as a white solid.

Elemental analysis calculated for C 23

H

25

N

5 *2 HCI: C: 62.41; H: 6.14; N: 15.82 Found: C: 62.43; H: 6.02; N: 15.63 'H NMR (CD30D) 8 8.62 (1H, 7.82 (2H, d, J=8Hz); 7.69 (1H, s); 7.46 (2H, d, J=8Hz); 7.27 (2H, t, J=8Hz); 7.06 (2H, d, J=8Hz); 6.92 (1H, t, J=8Hz); 5.67 (2H, 4.32 (2H, 3.82 (2H, d, J=13Hz); 3.40 (1H, tt, J=12,4Hz); 2.88 (2H, t, J=12Hz); 2.23 (2H, d, J=12Hz); 1.84 (2H, qd, J=12,4Hz).

FAB MS: 372 WO 97/38665 PCT/US97/06487 -255- EXAMPLE 128 [Benzyl(1-phenylpiperidin-4-yl)amino]methyl }imidazol-1vlmethyl)benzonitrile hydrochloride The title compound was prepared according to the procedure in Example 127, Step A, with benzyl(1-phenylpiperidin-4yl)amine (from Example 124) replacing 1-phenylpiperidin-4-ylamine.

The product was lyophilized from HC1 (aq) acetonitrile to give the title compound as a white solid.

Elemental analysis calculated for C 30

H

31 NSHCl*0.4 EtOAc: C: 71.16; H: 6.65; N: 13.13 Found: C: 71.25; H: 6.47; N: 12.84 FAB MS: 462 (MH EXAMPLE 129 [(1-phenylpiperidin-4-yl)pyridin-4ylmethylamino]methyl} imidazol-1 -ylmethyl)benzonitrile hydrochloride The title compound was prepared according to the procedure in Example 127, Step A, with (1-phenylpiperidin-4yl)pyridin-4-ylmethylamine (from Example 125) replacing 1phenylpiperidin-4-ylamine. The product was treated with HCI in ethyl acetate ethanol to give the title compound as a white solid.

Elemental analysis calculated for C 2 9

H

3 0

N

6 *4 HC1l0.65 EtOAc*0.6 H 2 0: C: 56.10; H: 6.02; N: 12.42 Found: C: 56.11; H: 6.02; N: 12.40 FAB MS: 463 WO 97/38665 PCT/US97/06487 -256- EXAMPLE 130 [Phenethyl( 1 -phenylpiperidin-4-yl)amino]methyl imidazol-1 ylmethyl)benzonitrile hydrochloride The title compound was prepared according to the procedure in Example 127, Step A, with phenethyl(1-phenylpiperidin-4yl)amine (from Example 126) replacing 1-phenylpiperidin-4-ylamine.

The product was treated with HC1 in ethyl acetate to give the title compound as a white solid.

Elemental analysis calculated for C 31

H

33 N5,3 HC1-0.65 H 2 0*0.3 EtOAc: C: 61.42; H: 6.82; N: 11.60 Found: C: 61.42; H: 6.68; N: 11.53 FAB MS: 476 EXAMPLE 131 4- {5-[2-(1-Phenylpiperidin-4-ylamino)ethyl]imidazol-1ylmethyl benzonitrile hydrochloride Step A: 4- 5-[2-(1-Phenylpiperidin-4-ylamino)ethyl]imidazol-1ylmethvl }benzonitrile hydrochloride 1-Phenylpiperidin-4-one (150 mg, 0.86 mmol) (from Example 123) and 4-[5-(2-aminoethyl)imidazol- -ylmethyl]benzonitrile (213 mg, 0.94 mmol) were dissolved in 1,2-dichloroethane (4 mL) and acetic acid (49 gL, 0.86 mmol) was added. The mixture was stirred for min at room temperature, then sodium triacetoxyborohydride (272 mg, 1.28 mmol) was added and the reaction mixture was stirred at room temperature for 18 hrs. Sat. Na 2

CO

3 (aq) (5 mL) was added, and the mixture was extracted with dichloromethane (3 x 10 mL). The combined organic extracts were dried over Na 2

SO

4 filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a gradient of WO 97/38665 PCT/US97/06487 -257dichloromethane 0.5% NH 4 OH 1 to 8% methanol to yield the product.

IH NMR (CDC1 3 6 7.63 (2H, d, J=8Hz); 7.51 (1H, 7.24 (2H, dd, J=9,7Hz); 7.12 (2H, d, J=8Hz); 6.93 (1H, 6.92 (2H, d, J=9Hz); 6.82 (1H, t, J=7Hz); 5.20 (2H, 3.63 (2H, dt, J=13,3Hz); 2.86 (2H, t, J=7Hz); 2.74 (2H, td, J=12,2Hz); 2.61 (2H, t, J=7Hz); 2.60-2.54 (1H, 2.10 (1H, br 1.92 (2H, d, J=13Hz); 1.46 (2H, qd, J=12,4Hz).

Treatment with HC1 in ethyl acetate gave the title compound as a white solid.

Elemental analysis calculated for C 24 H27N5-3 HCl*0.5 EtOAc: C: 57.94; H: 6.36; N: 13.00 Found: C: 57.80; H: 6.42; N: 13.00 FAB MS: 386 (MH EXAMPLE 132 2-[Benzyl( 1 -phenylpiperidin-4-yl)amino]ethyl imidazol- 1ylmethyl)benzonitrile hydrochloride Step A: 4-(5-{2-[Benzyl(1-phenylpiperidin-4yl)amino]ethyl }imidazol-1 -ylmethyl)benzonitrile hydrochloride Benzaldehyde (15 gL, 0.14 mmol) and phenylpiperidin-4-ylamino)ethyl]imidazol-1-ylmethyl }benzonitrile mg, 0.13 mmol) (from Example 131) were dissolved in 1,2dichloroethane (0.8 mL) and acetic acid (7 gL, 0.13 mmol) was added.

The mixture was stirred for 30 min at room temperature, then sodium triacetoxyborohydride (41 mg, 0.20 mmol) was added and the reaction mixture was stirred at room temperature for 18 hrs. Sat. Na 2

CO

3 (aq) (3 mL) was added, and the mixture was extracted with dichloromethane (3 x 5 mL). The combined organic extracts were dried over Na2SO 4 filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a gradient of ethyl acetate 0 to 10% methanol to yield the product.

WO 97/38665 PCT/US97/06487 258 'H NMR (CDC13) 8 7.55 (2H, d, J=8Hz); 7.40 (1H, d, J=lHz); 7.29-7.21 (7H, 6.94-6.90 (4H, 6.86 (1H, 6.83 (1H, tt, J=7,lHz); 4.86 (2H, 3.72 (2H, d, J=12Hz); 3.62 (2H, 2.71-2.60 (5H, 2.39 (2H, t, J=8Hz); 1.83 (2H, d, J=12Hz); 1.68 (2H, qd, J=12,4Hz).

Treatment with HC1 in ethyl acetate gave the title compound as a white solid.

Elemental analysis calculated for C 31

H

33

N

5 *3 HC1*0.3 H20*0.15 EtOAc: C: 62.87; H: 6.31; N: 11.60 Found: C: 62.87; H: 6.14; N: 11.60 FAB MS: 476 EXAMPLE 133 2-[3-(4-cyanobenzyl)-3H-imidazol-1-yl]-N-(4-cyanobenzyl)-N-(1phenvlpiperidin-4-yl)acetamide hydrochloride Step A: 4-Cvanobenzvl(1-phenvlpiperidin-4-vl)amine l-Phenylpiperidin-4-ylamine (0.50 g, 2.84 mmol) (from Example 123) and 4-cyanobenzaldehyde (0.74 g, 5.64 mmol) were dissolved in anhydrous methanol (10 mL) and acetic acid (0.97 mL, 17 mmol) was added. The mixture was stirred for 2 hrs at room temperature, then cooled to 0 oC (ice-water) and sodium cyanoborohydride (0.267 g, 4.25 mmol) was added, then the reaction mixture was stirred at room temperature for 2 hrs. The solvent was evaporated under reduced pressure and the residue was partitioned between sat. NaHCO 3 (aq) (50 mL) and dichloromethane (25 mL), and the organic layer was extracted. The aqueous phase was extracted with dichloromethane (2 x 25 mL). The combined organic extracts were dried over MgSO 4 filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexane 30% ethyl acetate to give the product as a white solid.

'H NMR (CDC1 3 8 7.62 (2H, 7.48 (2H, 7.25 (2H, 6.94 (2H, 6.83 (1H, 3.93 (2H, 3.65 (2H, dt); 2.78 (2H, td); 2.65 (1H, tt); 1.99 (2H, 1.54 (2H, qd); 1.41 (1H, br s).

WO 97/38665 PCT/US97/06487 -259- Step B: 4 -cyanobenzyl)-3H-imidazol- 1-yl]-N-(4cyanobenzyl)-N-(1-phenylpiperidin-4-yl)acetamide hydrochloride 4-Cyanobenzyl(l-phenylpiperidin-4-yl)amine (75 mg, 0.26 mmol), lithium 4 -cyanobenzyl)-3H-imidazol-4-yl]acetate (70 mg, 0.28 mmol), 1-hydroxybenzotriazole hydrate (52 mg, 0.38 mmol), 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (99 mg, 0.52 mmol), and N,N-diisopropylethylamine (67 gL, 0.38 mmol) were added to degassed DMF (3 mL) and the mixture was stirred for 18 hrs at room temperature then concentrated in vacuo. The residue was added to sat.

NaHCO 3 (aq) (5 mL) and extracted with dichloromethane (3 x 3 mL).

The combined organic extracts were dried over MgSO 4 filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane 2% methanol to give the product as a free base. This was lyophilized from HCI (aq) acetonitrile to give the title compound as a white solid.

Elemental analysis calculated for C 32

H

30

N

6 0-2.5 HCl 1.85 C: 60.04; H: 5.86; N: 13.13 Found: C: 60.08; H: 5.66; N: 13.09 'H NMR (CD30D) 8 8.99-8.92 (1H, 7.81-7.40 (14H, 5.59-5.53 (2H, 4.86-4.66 (3H, 4.40-3.69 (6H, 2.55-2.42 (2H, m); 2.15-2.02 (2H, m).

FAB MS: 515 (MH EXAMPLE 134 N-(1-benzylpiperidin-4-yl)-2-[3-(4-cyanobenzyl)-3H-imidazol-4vllacetamide hydrochloride The title compound was prepared according to the procedure in Example 123, Steps C D, with 1-benzylpiperidin-4-one WO 97/38665 PCTIUS97/06487 260 replacing 1-phenylpiperidin-4-one in Step C. The product was treated with HCI in ethyl acetate ethanol to give the hydrochloride salt.

Elemental analysis calculated for C 25

H

27

N

5 0*2 HCl 1 MeOH: C: 60.22; H: 6.42; N: 13.51 Found: C: 60.07; H: 6.53; N: 13.27 FAB MS: 414 (MH EXAMPLE 135 5-[(1-benzylpiperidin-4-ylamino)methyl]imidazol 1vlmethyl }benzonitrile hydrochloride To a stirred solution of 1-benzylpiperidin-4-ylamine (38 mg, 0.20 mmol) (from Example 134) and 4-(5-formylimidazol-1ylmethyl)benzonitrile (42 mg, 0.20 mmol) in methanol (1 mL) was added sodium cyanoborohydride (12 mg, 0.20 mmol). Acetic acid was added to adjust the mixture to pH 5.5, as judged by analyzing the solution with moist indicator paper. The resulting solution was stirred for 18 hrs, then sat. Na 2

CO

3 (aq) (5 mL) was added and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with water (10 mL), then brine (10 mL), then dried over Na 2

SO

4 filtered and concentrated in vacuo. The residue was chromatographed on silica, eluting with ammonia-saturated chloroform to give the product as a free base.

'H NMR (CDC1 3 7.61 (2H, 7.49 (1H, 7.48 (2H, 7.33-7.22 7.15 (2H, 6.95 (1H, 5.37 (2H, 3.59 (2H, 3.47 (2H, 2.78 (2H, 2.39 (1H, tt); 1.98 (2H, td); 1.73 (2H, 1.32 (2H, m); 1.41 (1H, br s).

Treatment of this with HC1 in ethyl acetate ethanol gave the hydrochloride salt.

Elemental analysis calculated for C 24

H

27

N

5 -3 HCl 1 EtOH-0.4 CH 2 C1 2 C: 55.15; H: 6.45; N: 12.18 Found: C: 55.29; H: 6.59; N: 12.02 FAB MS: 386 WO 97/38665 PCT/US97/06487 261 EXAMPLE 136 In vitro inhibition of ras farnesvl transferase Assays of farnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared as described by Schaber et J. Biol. Chem. 265:14701- 14704 (1990), Pompliano, et Biochemistry 31:3800 (1992) and Gibbs et al., PNAS U.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in a volume of 100 gl containing 100 mM N-(2hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM 3 H]-farnesyl diphosphate 3 H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 gg/ml FPTase at 31°C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB P-plate counter. The assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the 3 H]-FPP was utilized during the reaction period. Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.

Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10 iM ZnC1 2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 kl of 30% trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.

The compounds of the instant invention described in above Examples 1-135, except for Example 112C, were tested for inhibitory 262 activity against human FPTase by the assay described above and were found to have IC5o of EXAMPLE 137 In vivo ras farnesylation assay The cell line used in this assay is a v-ras line derived from either Rat 1 or NIH3T3 cells, which expressed viral Ha-ras p21. The assay is performed essentially as described in DeClue, J. E. et al., Cancer Research 51:712-717, (1991). Cells in 10cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is After 4 hours at 37 0 C, the cells are labelled in 3ml methionine-free DMEM supple-meted with 10% regular DMEM, 2% fetal bovine serum and 400mCi[ 35 S]methionine (1000Ci/mmol). After an additional 20 hours, the cells are lysed in lml lysis buffer NP40/20mM HEPES, pH 7.5/5mM MgC12/lmM aprotinen/2mg/ml leupeptin/2mg/ml antipain/0.5mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45min. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to lml with IP buffer (lysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, E. et al., J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4 0

C,

200ml of a 25% suspension of protein A-Sepharose coated with rabbit anti rat IgG is added for 45 min. The immunoprecipitates are washed four times with IP buffer (20nM HEPES, 20 pH 7.5/1mM EDTA/1% Triton X-100.0.5% deoxycholate/0.1%/SDS/0.1M NaC1) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to famesylated and nonfarnesylated ras proteins are Scompared to determine the percent inhibition of famesyl transfer to protein.

EXAMPLE 138 In vivo growth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of the Scompounds of the instant invention on the anchorage-independent growth of Rat 1 cells transformed with either a v-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.

Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 104 cells per plate (35mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer Both layers contain 0.1% methanol or an appropriate wR? concentration of the instant compound (dissolved in methanol at 1000 times the final [R:\LIBZZ]06267.doc:NJC 263 concentration used in the assay). The cells are fed twice weekly with 0.5m1 of medium A containing 0.1% methanol or the concentration of the instant compound. Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

a a.

a 9** a.

S.

a S a a a 9W a a a a. a a a.

S

(R)\L1BZZ]06267.doc:NJC

Claims

1. A compound which inhibits farnesyl-protein transferase of the formula A: (R 8 )r (R 9 )q R2 R 3 Al a 2 (CRla W (CRl b 2 X,(,l 2 Rl 4 R A wherein: R Ia and R Ib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, R 1 0 R 1 1 R 1 C(O)NR (RIO)2N-C(O)-, CN, N02, (R 1 O)2N-C(NRlO)-, RlOC(O)-, N3, -N(R'10)2, or R1 1 0C(O)NR c) unsubstituted or substituted Ci -C6 alkyl wherein the substitutent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R I 1 R I C(O)NR 10-, (R 10 CN, (RIO)2N-C(NRIO)-, RIOC(O)-, N3, -N(RIO)2, and R 1 1 0C(O)-NRIO-; Ric is selected from: a) hydrogen, b) unsubstituted or substituted Ci -C6 alkyl wherein the substitutent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R I S R 1 I C(O)NR 10-, (R I CN, WO 97/38665 PCTfUS97/06487 265 R 1 RIO0C(O)-, N3, -N(R 10)2, and R I I0C(O)-NR

10-, and c) unsubstituted or substituted aryl; R 2 and R 3 are independently selected from: H; unsubstituted or substituted Cl1 -8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or o r 1 substituted heterocycle, OR10, 0 0 wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C 1.-4 alkyl, b) (CH2)pOR 6 c) (CH2)pNR 6 R 7 d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C 1 -4 alkyl, h) SR 6 a, S(O)R 6 a, S02R 6 a, 2) C3-6 cycloalkyl, 3) OR 6 4) SR 6 a, S(O)R6a, or S02R6a, -NR 6 R 7 6) -N YR 7 0 -N YNR 7 R 7 a 0 WO 97/38665 WO 9738665PCT/US97/06487 266 8) -0 NR 6 R 7 0 9) -0 OR 6 0 "Y NR 6 R 7 0 11) -S0 2 -NR 6 R 7 R 6 12) -~N-S0-R 6a 13)R6 0 14) r R6 0 N 3 16) F, or 17) perfluoro-0 1 4 -alkyl; or R 2 and R 3 are attached to the same C atom and are combined to form -(CH2)u wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(CORIO)-; R 4 and R 5 are independently selected from H- and CH3; and any two of R 2 R 3 R 4 and R 5 are optionally attached to the same carbon atom; WO 97/38665 PCT/US97/06487 -267- R 6 R 7 and R 7 a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) unsubstituted aryl, substituted aryl, unsubstituted heteroaryl or substituted heterocycle, c) halogen, d) HO, e) R 1 1 0 f) -SO 2 R' or g) N(R10)2; or R 6 and R 7 may be joined in a ring; R 7 and R 7 a may be joined in a ring; R 6 a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) R 0 f) -S0 2 R 1 or g) N(R 10 )2; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, perfluoroalkyl, F, Cl, Br, R100-, R 1 1 S(O)m-, WO 97/38665 PCT/US97/06487 268 R 9 is Rl 0 C(O)NR (R 10 R 1 0 2N-C(NR CN, N02, R I N3, -N(R 10)2, or R I IOC(O)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, R I S R 1 I 0 C(O)NH-, (R 1 0 R I 0 2N- C(NRIO)-, CN, RIOC(O)-, N3, or R 1 0 0C(O)NH-; selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R I 1 R I 0 C(O)NR 10-, (R 1 0 )2NC(O)-, R 10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RlO)2, or R I I0C(O)NR 1 and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RIO0-, RI 1 RI OC(O)NR1O-, (Ri 0 R 1 0 2N-C(NRI0).., CN, R 1 0 N3, 102,or R I I0C(O)NR R 1 0 is independently selected from hydrogen, C 1 -C 14 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryi; R I Iis independently selected from C I -C6 alkyl and substituted or unsubstituted aryl; R1 2 is selected from: H; unsubstituted or substituted Ci-8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted alkyl, substituted aryl or substituted heterocycle is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C 1-4 alkyl, b) (CH2)pOR 6 WO 97/38665 WO 9738665PCTIUS97/06487 269 c) (CH2)pNR 6 R 7 d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C 1 -4 alkyl, h) SR 6 a, S(O)R 6 a, SO2R 6 a, 2) C3-6 cycloalkyl, 3) OR 6 4) SR 6 a, S(O)R 6 a, or SO2R 6 a, -NR 6 R 7 6) -N y R 7 0 R 6 7) 7 7 -N yNR Ra 0 8) -0O NR 6 R 7 0 9) -0 OR 6 y 0 "YNR 6 R 7 0 11) -S0 2 -NR 6 R 7 R 6 12) -NS R6 WO 97/38665 WO 9738665PCTIUS97/06487 270 0-r 0 N 3 F, perfluoro-0 1 4 -alkyl, or C 1 6 -alkyl; A 1 I and A 2 are independently selected from: a bond, -CH=CH-, -CE=C-, -C(O)NRIO-, -NRIOC(O)-, 0, -N(RIO)-, -S(0)2N(RIO)-, -N(RIO)S(0)2-, or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from 0, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X is a bond, -CH2-, -NR 6 or -S(=O)nv; *XI is a bond, -NR 6 -NR 6 or Y is selected from: a) hydrogen, WO 97/38665 WO 9738665PCTIUS97/06487 271 b) R 1 0 R 1 1 S(O)mn-, R I C(O)NRl10-, (R 10 CN, N02, (R 1 0 R 1 2 RI 0 N3, F, -N(R 10 or R' 1 0C(O)NR 10-, and c) unsubstituted or substituted C I -C6 alkyl wherein the substitutent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, RIO0-, RIOC(O)NR1O-, (RI 0 R 1 OC(O)- and R 1 0 0C(O)-; Z is an unsubstituted or substituted group selected from aryl and heterocycle, wherein the substituted group is substituted with one or more of the following: 1) Ci .4 alkyl, unsubstituted or substituted with: a) CI-4 aikoxy, b) NR 6 R 7 c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO, f) -S(O)mR 6 a, or g) -C(O)NR 6 R 7 2) aryl or heterocycle, 3) halogen, 4) OR 6 NR 6 R 7 6) CN, 7) N02, 8) CF3; 9) -S(O)mR 6 a, -C(O)NR 6 R 7 or 11) C3-C6 cycloalkyl; M is 0, 1 or 2; n is 0, 1,2, 3 or 4; p is 0,1, 2, 3or 4; q is I or 2; 272 r is 0 to 5, provided that r is 0 when V is hydrogen; s is 0Oorl1; t is 0Oorl1; u is 4 or v is 0,l1or2; wherein the definition of any substituent or variable at a particular location in formula A is independent of its definition elsewhere in formula; or a pharmaceutically acceptable salt thereof. 2. A compound which inhibits famesyl-protein transferase of the formula B: (R8)r F),q2R\ I la 2 la Ik b R(C:lbN-(CR' C )-Z V-A (C R 2 (C R' CR2p R 4 R B wherein: Riaand Ri are independently selected from: a) hydrogen, b) aryl, heterocycle, C 3 -Ciocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 1 0 0-, *:R 11 R"OC(O)NR 1 0 CN, NO 2 (R' 0 2 NC(N 1 R' 0 N 3 ~-N(R 1 0 2 or R' 1 0C(O)NR 10 c) unsubstitiited or substituted Ci-Coalkyl wherein the substituent on the 9 substituted CI-C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 *9 20 Clocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R' 0 R' 1 R' 0 C(O)NR 1 0 (R' 0 2 N- CN, (R' 0 2 N-C(NR 1 0 R' 0 N 3 -N(R' 0 2 and (R"lOC(O)-NRU-; RIC is selected from: [R:\LIBZZj06267.doc:NJC WO 97/38665 PCT/US97/06487 -273- a) hydrogen, b) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R 1 1 R10C(O)NR 10 (R 10 CN, (R10)2N-C(NR10)-, R1OC(O)-, R10OC(O)-, N3, -N(R 10 and R 1 1 OC(O)-NR 10 and c) unsubstituted or substituted aryl; R 2 and R 3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or R6R or R 6 substituted heterocycle, OR 10 O O wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C1-4 alkyl, b) (CH2)pOR 6 c) (CH2)pNR 6 R 7 d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C1-4 alkyl, h) SR 6 a, S(O)R 6 a, SO2R 6 a, 2) C3-6 cycloalkyl, 3) OR 6 4) SR 6 a, S(O)R 6 a, or SO2R 6 a, WO 97/38665 PCT1US97/06487 274 -NR 6 R 7 R 6 7)7 6) -N RRa 0 7) -O OR 6 0 0yNR 6 R 7 0 11) -S0 2 -NR 6 R 7 R 6 12) -NS R6 13)R6 0 14) r R6 0 N 3 16) F, or 17) perfluoro-0 1 4 -alkyl; or WO 97/38665 PCT/US97/06487 -275- R 2 and R 3 are attached to the same C atom and are combined to form (CH2)u wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and R 4 and R 5 are independently selected from H and CH3; and any two of R 2 R 3 R 4 and R 5 are optionally attached to the same carbon atom; R 6 R 7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) unsubstituted aryl, substituted aryl, unsubstituted heteroaryl or substituted heterocycle, c) halogen, d) HO, e) 11 0 f) -SO 2 R" or g) N(R 10 or R 6 -and R 7 may be joined in a ring; R 7 and R7a may be joined in a ring; R 6 a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, WO 97/38665 WO 9738665PCTIUS97/06487 276 e) >Rll 0 f) -S0 2 R 11 ,or g) N(R 1 0 )2; R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-Cl0 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 RlI 1 S(O)m-, (R 1 O)2NC(O)-, R 10 2N-C(NR CN, N02, R I N3, -N(R 10 or R I 0C (O)NR 1 and C) ClI -C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, R I 1 R I C(O)NH-, (R 1 R I 0 2N- C(NRIO)-, CN, RIOC(O)-, N3, -N(R 1 0 or R 10 0C(0)NH-; R 9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 RI 1 RIOC(O)NR10-, (R' 0 )2NC(O)-, R 10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(R 1 0 or R I I0C(O)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 RI IS R I C(O)NR (R 1 0 R 10 2N-C(NRIO)-, CN, RIOC(O)-, N3, 102,or R1 1 0C(O)NR 1 0-;1 R 1 0 is independently selected from hydrogen, C I -Cl14 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl; WO 97/38665 PCT/US97/06487 -277- R 11 is independently selected from C1-C6 alkyl and substituted or unsubstituted aryl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR10-, -NRIOC(O)-, O, -N(R1O)-, -S(0)2N(RO1)-, -N(R10)S(0)2-, or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X 2 is a bond, -CH2-, -NR 6 -C(=O)NR 6 -NR 6 -0- or Z is an unsubstituted or substituted group selected from aryl and heterocycle, wherein the substituted group is substituted with one or more of the following: 1) CI-4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6 R 7 c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO, f) -S(O)mR 6 a, or g) -C(O)NR 6 R 7 2) aryl or heterocycle, 278 3) halogen, 67 NRR,7 6) CN, 7) NO 2 8) CF 3 9) _S(O)m"R 6 a, -C(O)NR6R or 11) C 3 -C 6 cycloalkyl; mis 0,l1or 2; n is 0, 1,2, 3or 4; p is 0, 1,2, 3or 4; q is 1lor2; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 0Oorl1; t is 0 orl1; u is 4 or v is 0,l1or2; wherein the definition of any substituent or variable at a particular location in formula B is independent of its definition elsewhere in the formula; or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1 of the formula A: (R~r 9 2 R 3 ll (Ia 2 )A 2 (CR a A (C lb2) N 2)\X(CRlc 2 )v-Z AA wherein: [R-ALIBZZ]06267.doc:NJC WO 97/38665 PCT/US97/06487 -279- R a is independently selected from: hydrogen or C1-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloatkyl, R 1 0 -N(R10)2 or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R 10 0- and -N(RO0)2; Rc is selected from: a) hydrogen, b) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0 0-, R 1 1 R 10 C(O)NRO0-, (R 10 CN, (R 10 )2N-C(NR10)-, R 10 R 10 N3, -N(R 10 and R110C(O)-NR10-, and c) unsubstituted or substituted aryl; R 3 R 4 and R 5 are independently selected from H and CH3; .NR 6 R 7 R 2 is H: OR 10 O or C 1_ a lkvl inhranoh branched, -Y J -J U I.-.jy L, r.JUltJll.lI t JL unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 4) SR 6 a, SO2R 6 a, or NR 6 R 7 0 WO 97/38665 WO 9738665PCT/US97/06487 280 and any two of R 2 R 3 R 4 and R 5 are optionally attached to the same carbon atom; R 6 R 7 and R 7 a are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) C 1-4 alkoxy, b) halogen, or c) aryl or heterocycle; R 6 a is selected from: C 1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) C 1 -4 alkoxy, b) halogen, or c) aryl or heterocycle; R 8 is independently selected from: a) hydrogen, b) C I-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I-C6 perfluoroalkyl, F, Cl, R 10 R IOC(O)NR 10-, CN, N02, (R 1 0 )2N-C(NR R 1 0 -N(R 1 0 or R I I0C(O)NR 10-, and c) ClI-C6 alkyl substituted by C I-C6 perfluoroalkyl, R 1 0 0-, RIOC(O)NRIO-, (R 1 0 )2N-C(NRIO)-, RIOC(O)-, -N(Rl10)2, or R IIOC (O)NR R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, RIO0-, RI IS(O)m-, RIOC(O)NRIO-, CN, N02, (R 1 0 )2N-C(NRIO0>, RIOC(O)-, -N(R 1 0 or R I IOC(O)NR 10-, and WO 97/38665 PCT/US97/06487 -281 c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R 10 R 1 1 R10C(O)NR10,- CN, (R1 0 )2N-C(NR10)-, R10C(O)-, -N(R10)2, or R 1 1 0C(O)NR10-; R 1 0 is independently selected from hydrogen, C1-C 14 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl; R 1 1 is independently selected from C1-C6 alkyl and substituted or unsubstituted aryl; R 12 is selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted alkyl, suvbstituted aryl or substituted heterocycle is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C1-4 alkyl, b) (CH2)pOR 6 c) (CH2)pNR 6 R 7 d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C1-4 alkyl, h) SR 6 a, S(O)R 6 a, SO2R 6 a, 2) C3-6 cycloalkyl, 3) OR 6 4) SR6a, S(O)R 6 a, or SO2R 6 a, WO 97/38665 WO 9738665PCTIUS97/06487 282 -NR 6 R 7 R 6 6) 1 0 R 6 7) 77 N yNR Ra 0 8) -0o NR 6 R 7 0 9) -0O OR 6 0 'y NR 6 R 7 0 11) -S0 2 NR 6 R 7 R 6 12) -N S 2 R6 WO 97/38665 PCT/US97/06487 283 13) R 6 0 14) OR 6 0 N 3 16) F, 17) perfluoro-Cl.4-alkyl, or 18) Cl. 6 -alkyl; A 1 and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR 10 -NR1OC(O)-, O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X is -CH2- or WO 97/38665 PTU9/68 PCTfUS97/06487 284 XlI is a bond, -NR 6 -NR 6 or Y is selected from: a) hydrogen, b) R 10 R 1 1 R I C(O)NR 10-, (R'1 0 CN, N02, (R 1 0 )2N-C(NRIO)-, R 12 RIO0C(O)-, N3, F, -N(R 10)2, or R II 0C (O)NR 1 and c) unsubstituted or substituted Ci -C6 alkyl wherein the substitutent on the substituted Ci -C6 alkyl is selected from unsubstituted or substituted aryl, RIO00, R 1 OC (0)NRIO-, (Ri 0 R 1 OC(O)- and R 1 0 0C(O)-; Z is an unsubstituted or substituted group selected from aryl and heterocycle, wherein the substituted group is substituted with one or more of the following: 1) Ci -4 alkyl, unsubstituted or substituted with: a) C 1 4 alkoxy, b) NR 6 R 7 C) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO, f) S(O)mR 6 a, or g) -C(O)NR 6 R 7 2) aryl or heterocycle, 3) halogen, 4) OR 6 NR 6 R 7 6) CN, 7) N02, 8) CF3; 9) -S(O)mR 6 a, -C(O)NR 6 R 7 or 11) C3-C6 cycloalkyl; WO 97/38665 PCT/US97/06487 -285- m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; pis 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 0 or 1; t is 1; and v is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 4. The compound according to Claim 2 of the formula B: (R8 3 V-A(CRla 2 )nA 2 (CR a 2 n W (CR 1 b2) N-)(CRC2)v-Z R 4 R B wherein: Rla is independently selected from: hydrogen or C1-C6 alkyl; R b is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 -N(R10)2 or C2-C6 alkenyl, c) unsubstituted or substituted CI-C6 alkyl wherein the substitutent on the substituted Ci-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R 1 0 0- and -N(R 10 )2; WO 97/38665 PCT/US97/06487 286 Ric is selected from: a) hydrogen, b) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted Ci-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0 0-, R 1 1 R10C(O)NR10-, (R10)2N-C(O)-, CN, (R 10 )2N-C(NR10)-, R10C(O)-, R 10 N3, -N(RlO)2, and R11OC(O)-NR10-, and c) unsubstituted or substituted aryl; R 3 R 4 and R 5 are independently selected from H and CH3; .NR 6 R 7 R 2 is H; O or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 4) SR 6 a, SO2R 6 a, or NR 6 R 7 0 and any two of R 2 R 3 R 4 and R 5 are optionally attached to the same carbon atom; R 6 R 7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle; R 6 a is selected from: C1-4 alkyl or C3-6 cycloalkyl, WO 97/38665 WO 9738665PCT/US97/06487 287 unsubstituted. or substituted with: a) C 1-4 alkoxy, b) halogen, or c) aryl or heterocycle; R8 is independently selected from: a) hydrogen, b) C1I-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I-C6 perfluoroalkyl, F, Cl, R 1 0 RlIOC(O)NRl10-, CN, N02, (R 1 0 )2N-C(NR R 1 -N(Ri 0)2, or R I I0C(O)NR 1 and C) ClI-C6 alkyl substituted by C I-C6 perfluoroalkyl, R 10 0-, R 1 0 C(O)NRIO0, (RIO)2N-C(NRI R 1 OC(O)-, 102,or R I I0C(O)NR10-; R 9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, CI-C6 perfluoroaikyl, F, Cl, R 10 R 1 1 R I C(O)NR 10-, CN, N02, (Rl 0 )2N-C(NR10)-, RIOC(O)-, -N(R 1 0 or R1 1 0C(O)NR 10-, and C) C I -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Cl, R 1 0 R I S R I C (O)NR CN, (RIO)2N-C(NR10)-, RIOC(O)-, -N(R 1 0 or R I I0C(O)NR R 1 0 is independently selected from hydrogen, Cl1-C 14 alkyl, substituted or unsubstituted. benzyl and substituted or unsubstituted. aryl; R I is independently selected from C I -C6 alkyl and substituted or unsubstituted aryl; A and A 2 are independently selected from: a bond, -CH=CH-, WO 97/38665 PCT/US97/06487 -288- -C(O)NR10-, -NR1OC(O)-, 0, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X 2 is a bond, -CH2-, -NR 6 -C(=O)NR 6 -NR 6 -0- or Z is an unsubstituted or substituted aryl wherein the substituted aryl is substituted with one or more of the following: 1) C1-4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6 R 7 c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO, f) -S(O)mR 6 a, or g) -C(O)NR 6 R 7 2) aryl or heterocycle, WO 97/38665 PCT/US97/06487 -289- 3) 4) 6) 7) 8) 9) 11) halogen, OR 6 NR 6 R 7 CN, N02, CF3; -S(O)mR 6 a, -C(O)NR 6 R 7 or C3-C6 cycloalkyl; m is n is p is r is sis t is v is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; 0 to 5, provided that r is 0 when V is hydrogen; 0or 1; 1; and 0, 1 or 2; or a pharmaceutically acceptable salt thereof. The compound according to Claim 1 of the formula (R 8 )r V-A 1 (CR' b)p R 4 R wherein: Ra is selected from: hydrogen or C1-C6 alkyl; WO 97/38665 PCT/US97/06487 -290- R l b is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 -N(R10)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R 10 or -N(R 10)2; Ric is selected from: a) hydrogen, b) unsubstituted or substituted C -C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R1 0 0-, R 1 1 R 10 C(O)NR (R CN, (R 10 )2N-C(NRlO)-, R 10 R 1 0 N3, -N(R 10 and R 1 1 OC(O)-NR10-, and c) unsubstituted or substituted aryl; R 3 and R 4 independently selected from H and CH3; SNRR 7 R 2 is selected from H; OR 1 0 O or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 4) SR 6 a, SO2R 6 a, or NR 6 R 7 0 and R 2 R 3 and R 4 are optionally attached to the same carbon atom; WO 97/38665 PCT/US97/06487 -291 R 6 and R 7 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle; R 6 a is selected from: C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle; R 8 is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 RO1C(O)NR10-, CN, N02, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R 1 1 OC(O)NR 1 and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 0-, R1OC(O)NR10-, (R10)2N-C(NR10)-, RO1C(O)-, -N(R10)2, or R11OC(O)NR10-; R 9 a is hydrogen or methyl; R 10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; R 1 1 is independently selected from C1-C6 alkyl and aryl; R 12 is selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, WO 97/38665 WO 9738665PCTIUS97/06487 292 wherein the substituted alkyl, substituted aryl or substituted heterocycle is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C1-4 alkyl, b) (CH2)pOR 6 c) (CH2)pNR 6 R 7 d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C 1-4 alkyl, h) SR 6 a, S(O)R 6 a, SO2R 6 a, 2) C3-6 cycloalkyl, 3) OR 6 4) SR 6 a, S(O)R 6 a, or SO2R 6 a, -NR 6 R 7 6)6 0 7) 7 7 -N YNR Ra 0 WO 97/38665 WO 9738665PCTIJS97/06487 293 -0YNR 6 R 7 0 9) -0O OR 6 0 11) 12) 13) 14) 16) 17) rNR 6 R 7 0 -SO 2 NR 6 R 7 ~R6 0 N 3 F, petfluoro-C.- 4 -alkyl, or Cl-6-alkyl; A 1 I and A 2 are independently selected from: a bond, -CH=CH-, -eEC-, -C(0)NRIO-, -NR 1 0, or S(O)m; V is selected from: a) hydrogen, WO 97/38665 WO 9738665PCTfUS97/06487 294 b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 I is a bond, n is 0 and A 2 is S (O)m; X is -CH2- or X I is a bond, -NR 6 -NR 6 or Y is selected from: a) hydrogen, b) RIO0-, RIIS(O)m-, RIOC(0)NRIO-, (Rl 0 CN, N02, (R 1 0 )2N-C(NRIO)-, R 12 RIO0C(O)-, N3, F, -N(R 10 or R I I0C(O)NR c) unsubstituted or substituted C I -C6 alkyl wherein the substitutent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, RIO0-, RIOC(0)NRIO-, RIOC(O)- and RIOOC(O)-; Z is an unsubstituted or substituted aryl, wherein the substituted aryl is substituted with one or more of the following: 1) Ci 1.4 alkyl, unsubstituted or substituted with: a) Cl1 -4 alkoxy, b) NR 6 R 7 C) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO, 0) -S(O)mR 6 a, or WO 97/38665 WO 9738665PCTIUS97/06487 2) 3) 4) 6) 7) 8) 9) 11) 295 g) -C(O)NR 6 R 7 aryl or heterocycle, halogen, OR 6 NR 6 R 7 CN, N02, CF3; -S (O)mR 6 a, -C(O)NR 6 R 7 or C3-C6 cycloalkyl; m is n is p is r is v is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; and 0 to 5, provided that r is 0 when V is hydrogen; and 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 6. The compound according to Claim 2 of the formula (R 8)r p9a V -A(CRla2)A(CR 2 y i~b )p -X2 N(CRlc2 )V-Z R 4 R wherein: Ria is selected from: hydrogen or C1-C6 alkyl; WO 97/38665 PCT/US97/06487 -296- Rb is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 1 0 -N(R 10 )2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R 10 or -N(R10)2; Ric is selected from: a) hydrogen, b) unsubstituted or substituted C -C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R 1 1 R10C(O)NR10-, (R 0 CN, (R 10 )2N-C(NR10)-, R10C(O)-, R 1 0 N3, -N(R 10 and R11OC(O)-NR10-, and c) unsubstituted or substituted aryl; R 3 and R 4 independently selected from H and CH3; SN R 6 R 7 R 2 is selected from H; OR 10 O or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 4) SR 6 a, SO2R 6 a, or NR 6 R 7 0 and R 2 R 3 and R 4 are optionally attached to the same carbon atom; WO 97/38665 WO 9738665PCTIUS97/06487 297 R 6 and R 7 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) C 1 4 alkoxy, b) halogen, or c) aryl or heterocycle; R 6 a is selected from: Cl-4 alkyl or C3-.6 cycloalkyl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) halogen, or c) aryl or heterocycle; R 8 is independently selected from: a) hydrogen, b) C 1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1I-C6 perfluoroalkyl, F, Cl, RIO0-, RIOC(O)NRIO-, CN, N02, (RIO)2N-C(NRIO)-, RIOC(O)-, -N(R 1 0 or R I IOC(O)NR 10-, and c) C1I-C6 alkyl substituted by C 1-C6 perfluoroalkyl, R 1 0 0-, RIOC(O)NR 1 (R 1 0 )2N..C(NRI10>, RI OC(O)-, 102,or R I I0C(O)NR R 9 a is hydrogen or methyl; R 10 is independently selected from hydrogen, ClI-C 14 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl; R I is independently selected from C I -C6 alkyl and substituted or unsubstituted aryl; WO 97/38665 PCT/US97/06487 -298- Al and A 2 are independently selected from: a bond, -CH=CH-, -CC-, -C(O)NRO1-, -NR1OC(O)-, O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; X 2 is a bond, -CH2-, -NR 6 -C(=O)NR 6 -NR 6 -0- or Z is an unsubstituted or substituted aryl, wherein the substituted aryl is substituted with one or more of the following: 1) C1-4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6 R 7 c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO, f) -S(O)mR 6 a, or g) -C(O)NR 6 R 7 2) aryl or heterocycle, 3) halogen, 4) OR 6 NR 6 R 7 WO 97/38665 WO 9738665PCT[US97/06487 299 6) CN, 7) N02, 8) CF3; 9) -S(O)mR 6 a, 10) -C(O)NR 6 R 7 or 11) C3-C6 cycloalkyl; mnis 0, 1 or 2; n is 0, 1, 2, 3or 4; p is 0,1, 2, 3or 4;and r is 0 to 5, provided that r is 0 when V is hydrogen; and v is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 7. The compound according to Claim 1 of the formula E: H R 2 R 3 -CR 2\J N I C~lb 2 R 4 R R 8 E wherein: Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 1 0 0)2 or C2-C6 alkenyl, c) C I -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, RIO0-, or -N(R 10)2; WO 97/38665 PCT/US97/06487 -300- Rc is selected from: a) hydrogen, b) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R 1 1 RO1C(O)NR10-, (R10)2N-C(O)-, CN, (RO)2N-C(NRIO)-, R10C(O)-, R 1 OOC(O)-, N3, -N(R 10 and R11OC(O)-NR10-, and c) unsubstituted or substituted aryl; R 3 and R 4 independently selected from H and CH3; N R 6 R 7 R 2 is selected from H; OR10; O or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 4) SR 6 a, SO2R 6 a, or NR 6 R 7 and R 2 R 3 and R 4 are optionally attached to the same carbon atom; R 6 R 7 and R 7 a are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle; WO 97/38665 PCT/US97/06487 -301 R 6 a is selected from: C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle; R 8 is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 RO1C(O)NR10-, CN, N02, (R 10 )2N-C(NR1O)-, R 10 -N(R10)2, or R 1 1 OC(O)NR 10 and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 0-, R1OC(O)NR 10 (R 10 )2N-C(NR10)-, -N(R10)2, or R 1 1 0C(O)NR 10 R 10 is independently selected from hydrogen, C1-C14 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl; R 1 1 is independently selected from C -C6 alkyl and substituted or unsubstituted aryl; R 12 is selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted alkyl, suvbstituted aryl or substituted heterocycle is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C1-4 alkyl, b) halogen, c) CN, d) perfluoro-C1-4 alkyl, 2) C3-6 cycloalkyl, WO 97/38665 WO 9738665PCTIUS97/06487 302 3) OR 6 4) SR 6 a, S(O)R 6 a, Or SO2R 6 a, rR 6 0 6) OR 6 0 7) N 3 8) F, 9) perfluoro-0 1 4 -alkyl, or 510) 0 1 6 -alkyl; X is -CH2- or XI is a bond, or Y is selected from: a) hydrogen, N02, (R 1 0 )2N-C(NRIO)-, R 12 R 10 N3, F, -N(R 1 0 or R 11OC(O)NR c) unsubstituted or substituted C I -C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, R 1 0 R IOC(O)NR (RIO)2N-C(O)-, RIOC(O)- and RIOOC(O)-; Z is an unsubstituted or substituted aryl, wherein the substituted aryl is substituted with one or more of the following: 1) C 1 4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, WO 97/38665 WO 9738665PCTIUS97/06487 303 b) NR 6 R 7 c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO, f) -S(O)mR 6 a, or g) -C(O)NR 6 R 7 2) aryl or heterocycle, 3) halogen, 4) OR 6 5) NR 6 R 7 6) CN, 7) N02, 8) CF3; 9) -S(O)mR 6 a, 10) -C(O)NR 6 R 7 or 11) C3-C6 cycloalkyl; m is 0, 1 or 2; p is 0,1, 2, 3or 4;and v is 0, 1or 2; or a pharmaceutically acceptable salt thereof. 8. The compound according to Claim 2 of the formula F:. j b x2 N (0R 2 )V -z 6 (CR'b 2 RR R 8 F wherein: WO 97/38665 PCT/US97/06487 304 Rlb is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 -N(R10)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R 10 or -N(R 10)2; Ric is selected from: a) hydrogen, b) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R 1 1S(O)m-, RIOC(O)NR10-, (R10)2N-C(O)-, CN, (R 10 )2N-C(NR10)-, R 10 R 10 N3, -N(R 10 and R 1 1 OC(O)-NR 10 and c) unsubstituted or substituted aryl; R 3 and R 4 independently selected from H and CH3; NR 6 R 7 R 2 is selected from H; OR 10 O or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 4) SR 6 a, SO2R 6 a, or NR 6 R 7 and R 2 R 3 and R 4 are optionally attached to the same carbon atom; WO 97/38665 WO 9738665PCTIUS97/06487 305 R 6 R 7 and R 7 a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) C 1-4 alkoxy, b) halogen, or c) aryl or heterocycle; R 6 a is selected from: CJ-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Ci1 -4 alkoxy, b) halogen, or c) aryl or heterocycle; R 8 is independently selected from: a) hydrogen, b) C1I-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, ClI-C6 perfluoroalkyl, F, Cl, RIO0-, RIOC(O)NRIO-, CN, N02, (RIO)2N-C(NRIO)-, RIOC(O)-, RIOOC(O)-, -N(RIO)2, or R1 1 OC(O)NR 10-, and c) ClI-C6 alkyl substituted by C I-C6 perfluoroalkyl, R 1 0 0-, R 10 C(O)NRIO0, (RIO)2N-C(NRIO0>, RIOC(O)-, RIO0C(O)-, -N(RIO)2, or RI IOC(O)NRIO-; RIO is independently selected from hydrogen, CI-CI4 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl; R 1 1 is independently selected from C 1 -C6 alkyl and substituted or unsubstituted aryl; X 2 is -CH2-, -C(=O)NR 6 or -R- WO 97/38665 PCT/US97/06487 -306- Z is an unsubstituted or substituted aryl, wherein the substituted aryl is substituted with one or more of the following: 1) C1-4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6 R 7 c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO, f) -S(O)mR 6 a, or g) -C(O)NR 6 R 7 2) aryl or heterocycle, 3) halogen, 4) OR 6 NR 6 R 7 6) CN, 7) N02, 8) CF3; 9) -S(O)mR 6 a, -C(O)NR 6 R 7 or 11) C3-C6 cycloalkyl; m is 0, 1 or 2; p is 0, 1, 2, 3 or 4; and v is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 9. The compound according to Claim 1 wherein Xl is a bond. The compound according to Claim 2 wherein X 2 is a bond, -CH2-, -NR 6 -C(=O)NR 6 or WO 97/38665 WO 9738665PCT/US97/06487 307

11. A compound which inhibits farnesyl-protein transferase which is: N-1{ [1 -(4-Cyanobenzyl)- 1H-imidazol-5-yl] methyl (3 -methylphenyl>.. 4-hydroxy piperidine, N- -(4-Cyanobenzyl)-l1H-imidazol-5-yl]methyl -chlorophenyl)-4 hydroxy piperidine, N- -(4-Cyanobenzyl)- 1H-imidazol-5-yllmethyl methylbenzyl)isonipecotic acid methyl ester, N- (4-Cyanobenzyl)- 1H-imidazol-5 -yl]methyl (3-methylphenyl)-4 hydroxy piperidine, N- -(4-Cyanobenzyl)- 1H-imidazol-5-yl]acetyl methylbenzyl)isonipecotic acid methyl ester, N- I 1-(4-Cyanobenzyl)- 1 H-imidazol-5-yl]acetyl 1 methylbenzyl))isonipecotic acid methyl ester, N- I [1I -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]acetyl I methylbenzyl))isonipecotic acid methyl ester, N- I 1- (4-Cyanobenzyl)- 1 H-imidazol-5-yl] acetyl (2,4- dichlorobenzyl))isonipecotic acid methyl ester, N- f f[1 -(4-Cyanobenzyl)- I H-imidazol-5-yl]acetyl methoxybenzyl)isonipecotic acid methyl ester, N- I -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]acetyl 1 1- naphthylmethyl)isonipecotic acid methyl ester, WO 97/38665 WO 9738665PCT/US97/06487 308 N- 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] acetyl chlorobenzyl)isonipecotic acid methyl ester, N- I [1I -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] acetyl (2,3- dichlorobenzyl)isonipecotic acid methyl ester, N-1{ 1-(4 Cyanobenzyl)- 1H-imidazol-5 -yl-aminocarbonyl methylbenzyl) isonipecotic acid methyl ester, 2(R,S [1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]2-(4- cyanobenzyl) I acetyl-4-(2-methylbenzyl)-isonipecotic acid methyl ester, N-I [1I -(Naphth-2-ylmethyl)- 1 H-imidazol-5-yl]acetyl inethylbenzyl)isonipecotic acid methyl ester, N- I -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]methyl -4-methoxymethyl-4- (2-methylbenzyl) piperidine, N- I [1I- (4-Cyanobenzyl)- 1 H-imidazol-5-yl] acetyl)I 4-methoxymethyl-4- (2-methylbenzyl) piperidine, N-1{ [1 -(4-Cyanobenzyl)- IH-imidazol-5-yl] acetyl I-4-hydroxymethyl-4- (2-methylbenzyl) piperidine, N-1 [IE (4-Cyanobenzyl)- 1 H-imidazol-5 -yl] ethyl methylbenzyl)isonipecotic acid methyl ester, N- -(4-Cyanobenzyl)- 1H-imidazol-5-ylimethyl -trans-4-(3- methylphenyl)-3 -hydroxypiperidine, N- I [I1 -(4-Cyanobenzyl)- 1 1--imidazol-5-yljinethyl I -trans-4- (3- methylphenyl)-3 methoxy piperidine, WO 97/38665 WO 9738665PCTIUS97/06487 309 N- -(4-cyanobenzyl)- 1H-imidazol-5-yllmethyl -trans-4- (3- methylphenyl)-3 benzyloxy piperidine, 1- [2(R,S)-Amino-3 -(2-tetradecyloxyphenyl)propyl]-4-(2- methylbenzyl)isonipecotic acid methyl ester, N-2-(S)-aminolauroyl-4-( 1-napthylmethyl) isonipecotic acid methyl ester, 4- (B enzoxazolidin-2-one- l-yl)-l -[r1 -(4-cyanobenzyl)-5 imidazolylacetyl]piperidine, 1,2-Dihydro-4(H)-3, 1-benzoxazin-2-one- l-yl)-l -(4-cyanobenzyl)- -imidazolylacetylipiperidine, 1,2-Dihydro-4(H)-3, 1-benzoxazin-2-one- l-yl)-l -(4-cyanobenzyl)- -imidazolylmethyilpiperidine, N- [2-f (4-Cyanobenzyl)-5-imidazolyl I ethyl] -4-carbamoyl- 1 phenylpiperidine hydrochloride or 4- [2-f11-(4-Cyanobenzyl)-5-imidazolyl ethyl]- -1 -phenylpiperidine hydrochloride 4-f{ 5- [4-Hydroxymethyl-4- (3-trifluorornethoxybenzyl)-piperidine- 1- ylrnfethyl]imidazol- 1-ylmethyl }benzonitrile 4-15- [4-Hydroxymethyl-4- (3 -trifiuoromethoxybenzyl) -piperidine- 1 ylmethyl]-2-methylimidazol- 1 -ylmethyl I benzonitrile 4- 5- [4-Hydroxymethyl-4- (3 -trifluoromethylbenzyl)-piperidine- 1 ylmethyl]imidazol- 1 -ylmethyl I}benzonitrile 4-1{5- [4-Hydroxymethyl-4- (3 -trifluoromethylbenzyl)-piperidine- 1 ylrnethyl]-2-methylimidazol- 1 -ylmethyl I benzonitrile WO 97/38665 WO 9738665PCTIUS97/06487 310 4- f 5 [4-I-ydroxymethyl-4-(2-trifluoromethylbenzyl)-piperidine- 1- ylmethyl]imidazol- 1-ylmethyl }benzonitrile 4-1{5-[4-Hydroxymethyl-4-(2-methylbenzyl)piperidine 1- ylmethyllimidazol- 1 -ylmethyl I benzonitrile 4-1{5-[4-Hydroxymethyl-4-(3-methylbenzyl)piperidine- 1- ylmethyljimidazol- 1 -ylmethyl I benzonitrile 4-1{5-[4-Hydroxymethyl-4- (3-methylbenzyl)piperidine- I -ylmethyl] 2-methylimidazob- 1 -ylmethyl I benzonitrile [4-Hydroxymethyl-4- (3 -methylbenzyl)piperidine- 1 -yl]-2- oxoethyl I imidazol- 1 -ylmethyl)benzonitrile 4-{f 5- [4-Hydroxymethyl-4- (3-methylbenzyl)piperidine- 1 carbonyl]imidazol- 1 -ylmethyl I benzonitrile 4-1{5- [4-Hydroxymethyl-4-(2-methylbenzyl)piperidine- 1 carbonyl]imnidazol- 1 -ylmethyl benzonitrile 4- 15 5- [4-Hydroxymethyl-4-(3-chlorobenzyl)-piperidine- 1 -ylmethyl] 2-methylimidazol- 1 -ylmethyl I}benzonitrile 4-1{5- [4-Hydroxymethyl-4- (2-cyanobenzyl)-piperidine- 1 -ylmethyl] -2- methylimidazol- 1 -ylmethyl J benzonitrile 4- [4-Hydroxyrnethyl-4- (3 -cyanobenzyl)-piperidine- I -ylmethyl] -2- methylimidazol- 1 -ylmethyl I benzonitrile 4-1{5- [4-Hydroxymethyl-4-(4-cyanobenzyl)piperidine- 1 -ylmethyl 1-2- methylimidazol- 1 -ylmethyl I benzonitrile 4- f 5- [4-Hydroxymethyl-4-(2,5-dimethylbenzyl)piperidine- 1 ylmethyl] -2-methylimidazol- 1 -ylmethyl I}benzonitrile WO 97/38665 WO 9738665PCT/US97/06487 311 4-1{5- [4-Hydroxymethyl-4-(2 ,5 -dichlorobenzyl)piperidine- 1 ylmethyl] -2-methylimidazol- 1 -ylmethyl I benzonitrile 4- [4-Hydroxymethyl-4- (3,5 -dimethylbenzyl)piperidine- 1 ylmethyl]-2-methylimidazol- 1 -ylmethyl benzonitrile 4-Hydroxymethyl [3 ,5-bis (trifluoromethyl)benzyl] piperidine- 1 -ylmethyl I -2-methylimidazol- 1 -ylmethyl)benzonitrile 4-15- 14-Hydroxymethyl-4-(2, 3 -dichlorobenzyl)piperidine- 1 ylmethyl] -2-methylimidazol- 1 -ylmethyl I benzonitrile 4- [5-(4-Hydroxymethyl-4-benzylpiperidine- 1 -ylmethyl)-2- methylimidazol- 1 -ylmethyl]benzonitrile 4-1{5- [4-Hydroxymethyl-4- (3 -trifluoromethoxybenzyl)-piperidine- 1 ylmethyl] -2-methylimidazol- 1 -ylmethyl I benzamide 4- f5- [4-Methoxymethyl-4-(3-methylbenzyl)-piperidine- 1 ylmethyl] imidazol- I1-ylmethyl) benzonitrile [4-Methoxymethyl-4- (3-methylbenzyl)-piperidine- 1 -ylmethyll 2-methylimidazol- 1 -ylmethyl I benzonitrile 4-1 [4-Methoxymethyl-4- (3 -trifluoromethoxybenzyl)-piperidine- I1- ylmethyllimidazol- 1 -ylmethyl }benzonitrile 4-f15-[4-Methoxymethyl-4- (3-trifluoromethoxybenzyl)-piperidine- 1- ylmethyl] -2-methylimidazol- 1 -ylmethyl I benzonitrile 5- [4-Methoxymethyl-4-(2-trifluoromethoxybenzyl)-piperidine- 1 ylmethyljimidazol- 1 -ylmethyl I benzonitrile 4-15- [4-Methoxymethyl-4-(2-trifluoromethoxybenzyl)-piperidine- 1 ylmethyl] -2-rnethylirnidazol- 1 -ylmethyl I}benzonitrile WO 97/38665 WO 9738665PCTIUS97/06487

312- 4- [4-Methoxymethyl-4-(3 -cyanobenzyl)-piperidine- I -ylmethyl] -2- methylimidazol- 1 -ylmethyl I benzonitrile [4-Methoxymethyl-4-(3-methylbenzyl)-piperidine- Il-yl] -2- oxoethyl I imidazol- I -ylmethyl)benzonitrile 4- {5-[4-Methoxymethyl-4-(3.-methylbenzyl)piperidine- I1- carbonyl] imidazol- 1 -ylmethyl I}benzonitrile Methyl 1- [3 -(4-cyanobenzyl)-3 H-imidazol-4-ylmethyl]-4-(3 methylbenzyl)piperidine-4-carboxylaie Methyl 1- [3-(4-cyanobenzyl)-3 H-imidazol-4-ylmethyl] (3- trifluoromethoxybenzyl)piperidine-4-carboxylate Methyl 1- [3-(4-cyanobenzyl)-2-methyl- 3H-imidazol-4-ylmethyl] -4- (3 -trifluoromethoxybenzyl)piperidine-4-carboxylate Methyl 1- [3 -(4-cyanobenzyl)-3H-imidazol-4-ylmethyl] trifluoromethoxybenzyl)piperidine-4-c arb oxyl ate Methyl 1- [3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-(3 cyanobenzyl)piperidine-4-carboxylate Methyl 1- [3 -(4-cyanobenzyl)- 3H-imidazol-4-ylmethyl]-4- [3- (benzyloxycarbonylaminomethyl)benzyllpiperidine-4-carboxylate Methyl 1- (4-cyanobenzyl)- 3H-imidazol-4-ylrnethyl]-4- [3- (aminomethyl)benzyllpiperidine-4-carboxylate Ethyl 1- [3-(4-cyanobenzyl)-2-methyl-3H-imidazol-4-ylmethyl] [3- (methanesulfonylaminomethyl)benzyl]piperidine-4-carboxylate Ethyl 1- [3 -(4-cyanobenzyl)-2-methyl- 3H-imidazol-4-ylmethyl] (3- nitrobenzyl)piperidine-4-carboxylate WO 97/38665 WO 9738665PCTIUS97/06487 313 Ethyl 1- [3 4 -cyanobenzyl)-2-methyl-3H-imidazol-4-ylmethyl] (3- methanesulfonylaminobenzyl)piperidine-4-carboxylate Ethyl 1- [3 4 -cyanobenzyl)-3H-imidazol-4-ylmethyl] -4- benzylpiperidine-4-carboxylate Methyl 1 4 -cyanobenzyl)-3H-imidazol-4-ylmethyl-4- cyclopropylmethylpiperidine-4-carboxylate Methyl 1- [3 4 -cyanobenzyl)-3H-imidazo-4-ylcarbonyl] (3- methylbenzyl)piperidine-4-carboxylate Methyl 1- [3 4 -cyanobenzyl)-3H-imidazo1-4-ylcarbonyly4-(2- methylbenzyl)piperidine-4-carboxylate Methyl 1- 3 4 -cyanobenzyl)-3H-imidazol-4-ylacetyl] trifluoromethoxybenzyl)piperidine-4-carboxylate Methyl 1 4 -cyanobenzyl)--3H-imidazol-4-ylacetyly4(2- trifluoromethoxybenzyl)piperidine-4-carboxylate Methyl 1- 4 -cyanobenzyl)-3H-imidazol-4-ylacetyl] (3- cyanobenzyl)piperidine-4-carboxyl ate Methyl 1- [3-(4-cyanobenzyl)-3H-imidazol-4-ylethyl]4-(3 methylbenzyl)piperidine-4-carboxylate ()Methyl 2- (n-butyl)-1- [3-(4-cyanobenzyl)-3H-imidazol-4- ylmethyl] 4 -(3-methylbenzyl)piperidine-4-carboxylate I -[3-(4-Cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-(3- methylbenzyl)isonipecotamide 1- [3-(4-Cyanobenzyl)-3 H-imidazol-4-ylmethyl] (2- methylbenzyl)isonipecotamnide WO 97/38665 PTU9/68 PCT[US97/06487 314 1- [3-(4-CyanobenzyI)-3H-imidazol-4-ylacetyl]-4-(3-methyl. benzyl)isonipecotamide 1- (4-Cyanobenzyl)-3H-imidazol-4-ylacetylp4(2-methyl- benzyl)isonipecotamide 1- (4-Cyanobenzyl)-3 H-imidazol-4-ylcarbonyl]-4-.(3-methyl- benzyl)isonipecotamide 1- [3 4 -Cyanobenzyl)-3H-imidazol-4-ylcarbonyl] -4-(2-methyl. benzyl)isonipecotamide 1- [3-(4-Cyanobenzyl)-3H-imidazol-4-yI methyl] (3- methylbenzyl)piperidine-4-carbonitrile 1- [3-(4-Cyanobenzyl)-3H-imidazol-4-ylmethyl] methylbenzyl)piperidine-4-carbonitrile 1-[1 3 -(4-Cyanobenzyl)-3H-imidazol-4-ylmethy] methylbenzyl)piperidine-4-carbonitrile 1- (4-Cyanobenzyl)-2-methyl- 3H-imidazol-4-ylrnethyl]-4 (3- methylbenzyl)piperidine-4-carbonitrile 1- 3 4 -Cyanobenzyl)-3H-imidazol-4-ylcarbonyliI-4- (3- methylbenzyl)piperidine-4-carbonitrile 1- 4 -Cyanobenzyl)-3H-imidazol-4-ylcarbonyl] (2- methylbenzyl)piperidine-4-carbonitrile 1- [3-(4-Cyanobenzyl)-3H-imidazol-4-ylacetyl (3- methylbenzyl)piperidine-4-carbonitrile 1- [3-(4-Cyanobenzyl)-3H-imidazol-4-ylacetyl] methylbenzyl)piperidine-4-carbonitrile WO 97/38665 WO 9738665PCTIUS97/06487 315 1- [3-(4-Cyanobenzyl)-3H-irnidazol-4-ylethyl] methylbenzyl)piperidine-4-carbonitrile 1- [3-(4-Cyanobenzyl)-3H-imidazol-4-ylethyl] methylbenzyl)piperidine-4-carbonitrile 4-15- [4-Hydroxymethyl-4- 4 -methylpyridin-2-ylmethyl)-piperidine- 1 -ylmethyl] -2-methylimidazol- 1 -ylmelihyl I benzonitrile 4- f 5- 4 -Hydroxymethy-4-(6-methypyidin-2-ylmethyl)-piperidine- 1 -ylmethyll -2-inethylimidazol- 1 -ylmethyl I benzonitrile 4- 1 5- [4-Hydroxymethyl-4- (2-methylpyridin-4-ylmethy)-piperidine-~ 1 -ylmethyl] -2-methylimidazol- 1 -ylmethyl I benzonitrile 4-15- [4-Hydroxymethyl-4-(4-chloropyridin-2-ylmethyl)-piperidine- 1 -ylmethyl] -2-methylimidazol- 1 -ylmethyl I benzonitrile 4-1{5- [4-Methoxymethyl-4-(6-methylpyridin-2-ylmethyl) -piperidine- 1 -ylmethyl]imidazol- 1 -ylmethyl }benzonitrile 4-15- [4-Hydroxymethyl-4- (6-hydroxypyridin-2-ylmethyl)- piperidine- I ylmethyl]-2-methylimidazol- I -ylrnethyl I benzonitrile 4- (4-Hydroxymethyl-4-quinolin-2-ylmethyl-piperidine- 1 ylmethyl)-2-methylimidazol- 1 -ylmethyl]benzonitrile Methyl 1- [3 -(4-cyanobenzyl)-3 H-imidazol-4-ylrnethyl]-4-(3- methylbenzoyl)piperidine-4-carboxylate 1- [3-(4-Cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-(3- methylbenzoyl)piperidine 1- [3-(4-Cyanobenzyl)-3H-imidazol-4-ylmethyl] (hydroxy-m- tolylrnethyl)piperidine WO 97/38665 WO 9738665PCTIUS97/06487 316 4- f 5.-[4-Hydroxymethyl-4- (3-tolylsulfanyl)piperidine- I1- ylmethyl]imidazol- 1 -ylmethyl benzonitrile 4-f 5- [4-Methoxymethyl-4-(3-tolylsulfanyl)piperidine- 1 ylmethyllimidazol- 1 -ylmethyl }benzonitrile 4-1{5- [4-Methoxymethyl-4-(3-tolylsulfinyl)piperidine- 1 ylmethyl]imidazol- 1 -ylmethyl I benzonitrile 4- 5-14-Methoxymethyl-4-(3-tolylsulfonyl)piperidine- I1- ylrnethyllimidazol- 1 -ylmethyl I benzonitrile 1- [3-(4-Cyanobenzyl)-3 H-irnidazol-4-ylmethyl] methylphenylamino)isonipecotamide Ethyl 1- [3-(4-Cyanobenzyl)- 3H-imidazol-4-ylmethyl] (3- methylphenylamino)piperidine-4-carboxylate 1- [3-(4-Cyanobenzyl)-3H-imidazol-4-ylmethyl] -4-hydroxyrnethyl-4- (3-methylphenylamino)piperidine 0-1 1- [3-(4-Cyanobenzyl)- 3H-imidazol-4-ylmethyl] methylphenylamino)piperidyl-4-methyl I carbamate 1- [3 -(4-Cyanobenzyl)- 3H-imidazol-4-ylmethyl] (3- methylphenylamino)piperidyl-4-methylurea 1- [3-(4-Cyanobenzyl)-3 H-iinidazol-4-ylmethyl]-4-(3- methylphenylamino)piperidyl-4-methylsulfamide 4-15 (Hydroxydiphenylmethyl)piperidin- I -ylmethyl] imidazol- 1 ylmethyl I benzonitrile (Hydroxydiphenylmethyl)piperidine- 1 -carbonyllimidazol- 1 ylmethyl I}benzonitrile WO 97/38665 WO 9738665PCT/US97/06487 317 {2-[4-(Hydroxydiphenylmethyl)piperidin- 1 -ylII-2-oxoethyl -3H- imidazol- 1 -ylmethyl)benzonitrile 1 -(Piperidin-4-ylmethyl)--5-(4-cyanobenzyl)imidazole 1 -Phenylpiperidin-4--ylmethyl)-5- (4-cyanobenzyl)imidazole 1-l (2-Methylphenyl)piperidin-4-ylmethyl)-5-(4- cyanobenzyl)imidazole 1- (1-(2-Chlorobenzoyl)piperidin-4-ylmethyl)-5- (4- eyanobenzyl)imidazole 1 -Chlorobenzoyl)piperidin-4-ylmethyl)-5-(4- cyanobenzyl)imidazole 1 (3-Chlorobenzenesulfonyl)piperidin-4-ylrnethyl)- 5-(4- cyanobenzyl)imidazole 1 -(3-Chlorobenzyl)piperidin-4-ylmethyl)-5-(4- cyanobenzyl)imidazole 2- [3-(4-Cyanobenzyl)- 3H-imidazol- 1 (1 -phenylpiperidin-4- yl)acetamide 2- (4-Cyanobenzyl)-3H-imidazol- 1l-yl] -N-benzyl-N-( phenylpiperidin-4-yl)acetamide 2- (4-Cyanobenzyl)-3H-imidazol- Il-yl] (1 -phenylpiperidin-4-yl)- N-pyridin-4-ylmethylacetamide WO 97/38665 WO 9738665PCT/US97/06487 318 2- [3-(4-Cyanobenzyl)-3H-imidazol- l-yl] -N-phenethyl-N-( 1- phenylpiperidin-4-yl)acetamide 4-f 5- -Phenylpiperidin-4-ylamino)methyl]imidazol- 1- ylmethyl I benzonitrile [B enzyl(l1-phenylpiperidin-4-yl)amino] methyl imidazol- 1- ylmethyl)benzonitrile -Phenylpiperidin-4-yl)pyridin-4- ylmethylaminolmethyl I imidazol- 1 -ylmethyl)benzonitrile 4-(5-1I [Phenethyl(l1-phenylpiperidin-4-yl)amino]methyl I imidazol- 1- ylmethyl)benzonitrile 4- 5-[2-(l1 -Phenylpiperidin-4-ylamino)ethyl]imidazol- 1 ylmethyl I benzonitrile [B enzyl( 1 -phenylpiperidin-4-yl)amino] ethyl I imidazol- 1 ylmethyl)benzonitrile 2- [3-(4-Cyanobenzyl)-3H-imidazol- 1 -yl] -N-(4-cyanobenzyl)-N-( 1- phenylpiperidin-4-yl)acetamide 1-B enzylpiperidin-4-yl)-2- [3 (4-cyanobenzyl)- 3 H-imidazol-4- ylacetamide and 4- [(1-Benzylpiperidin-4-ylamino)methyl] imidazol- 1- ylmethyl I}benzonitrile or a pharmaceutically acceptable salt or optical isomer thereof. The compound according to Claim 9 which is: WO 97/38665 PCT/US97/06487 -319- N- [1-(4-Cyanobenzyl)-1H-imidazol-5-yl]methyl 4 3 -methylphenyl)- 4-hydroxy piperidine NC NOH or a pharmaceutically acceptable salt or optical isomer thereof. 11. The compound according to Claim 9 which is: 4- {5-[4-Hydroxymethyl-4-(3-trifluoromethoxybenzyl)-piperidine-1- ylmethyl]imidazol- 1-ylmethyl }benzonitrile NC OH OCF 3 or a pharmaceutically acceptable salt or optical isomer thereof. 12. The compound according to Claim 9 which is: 4- 5-4-Hydroxymethyl-4-(4-chloropyridin-2ylmethyl)piperidine- 1- ylmethyl]-2-methylimidazol-1-ylmethyl }benzonitrile NC -OH or a pharmaceutically acceptable salt or optical isomer thereof. WO 97/38665 PCTIUS97/06487 320 13. The compound according to Claim 9 which is: 4-f 4 -Methoxymethyl-4-(3-tolylsulfanyl)piperidine-1- ylmethyl]imidazol- I -ylmethyl I}benzonitrile trifluoroacetate salt NC N CH 3 or a pharmaceutically acceptable salt or optical isomer thereof. 14. The compound according to Claim 9 which is: 1- [3 -(4-Cyanobenzyl).-3H-imidazol -4-ylmethyl] -4-hydroxymethyl methylphenylamino)piperidine NC -N- 0OH OH 3 or a pharmaceutically acceptable salt or optical isomer thereof. The compound according to Claim 9 which is: 1- (4-Cyanobenzyl)-3H-imidazol-4-ylmethyl] methylphenylamino) -piperidyl-4-methylcarbamate WO 97/38665 PCT/US97/06487 -321 0 NH 2 NC N N CH, or a pharmaceutically acceptable salt or optical isomer thereof. 16. The compound according to Claim 9 which is: 1-(1-(3-Chlorobenzoyl)piperidin-4-ylmethyl)-5-(4- cyanobenzyl)imidazole Cl NCN N or a pharmaceutically acceptable salt or optical isomer thereof. 17. The compound according to Claim 9 which is: 4- 5- [(1-Benzylpiperidin-4-ylamino)methyl]imidazol-1- ylmethyl }benzonitrile NC N" N H N or a pharmaceutically acceptable salt or optical isomer thereof. 18. A compound which inhibits famesyl-protein transferase, substantially as hereinbefore descried with reference to any one of the Examples. 19. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound according to any one of claims 1 to 18. A pharmaceutical composition made by combining the compound according to any one of claims 1 to 18 and a pharmaceutically acceptable carrier. 21. A process for making a pharmaceutical composition comprising combining a compound according to any one of claims 1 to 18 and a pharmaceutically acceptable carrier. 22. A method for inhibiting famesyl-protein transferase, which method comprises administering to a mammal a therapeutically effective amount of a compound according to any one of claims 1 to 18 or of a composition of claim 19. 23. A compound according to any one of claims 1 to 18 or a composition according to claim 19 when used to inhibit famesyl-protein transferase. 24. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for inhibiting farnesyl-protein transferase. A method for treating cancer, which method comprises administering to a mammal a therapeutically effective amount of a compound according to any one of claims 1 S to 18 or of a composition according to claim 19. 26. A compound according to any one of claims 1 to 18 or a composition according to claim 19 when used to treat cancer. 27. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for treating cancer. S 28. A method for treating neurofibromin benign proliferative disorder, which S method comprises administering to a mammal a therapeutically effective amount of a o* compound according to any one of claims 1 to 18 or of a composition according to claim 19. 29. A compound according to any one of claims 1 to 18 or a composition according to claim 19 when used to treat neurofibromin benign proliferative disorder. 30. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for treating neurofibromin benign proliferative disorder. 31. A method for treating blindness related to retinal vascularisation, which method comprises administering to a mammal a therapeutically effective amount of a compound according to any one of claims 1 to 18 or of a composition according to claim 19. 32. A compound according to any one of claims 1 to 18 or a composition according Sto claim 19 when used to treat blindness related to retinal vascularisation. [R:\LIBZZ]06267.doc:NJC 323 33. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for treating blindness related to retinal vascularisation. 34. A method for treating infections from hepatitis delta and related viruses, which method comprises administering to a mammal a therapeutically effective amount of a compound according to any one of claims 1 to 18 or of a composition according to claim 19. A compound according to any one of claims 1 to 18 or a composition according to claim 19 when used to treat infections from hepatitis delta and related viruses. 36. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for treating infections from hepatitis delta and related viruses. 37. A method for preventing restenosis, which method comprises administering to a mammal a therapeutically effective amount of a compound according to any one of claims 1 to 18 or of a composition according to claim 19. 38. A compound according to any one of claims 1 to 18 or a composition according to claim 19 when used to prevent restenosis. 39. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for preventing restenosis. A method for treating polycystic kidney disease, which method comprises i: administering to a mammal a therapeutically effective amount of a compound according to 2 any one of claims 1 to 18 or of a composition according to claim 19. 41. A compound according to any one of claims 1 to 18 or a composition according to claim 19 when used to treat polycystic kidney disease. a 42. Use of a compound according to any one of claims 1 to 18 in the manufacture of o a medicament for treating polycystic kidney disease. Dated 24 November, 1999 25 Merck Co., Inc. a. Patent Attorneys for the Applicant/Nominated Person a a SPRUSON FERGUSON [R:\LIBZZ]06267.doc:NJC